TWI449711B - Hcv inhibitors - Google Patents

Description

Hepatitis C virus (HCV) inhibitor Cross-references to related applications

This application claims the benefit of U.S. Patent Application Serial No. 60/695,767, filed on Jun.

Field of invention

The present invention relates to compounds which inhibit HCV replication and thus contribute to the treatment of hepatitis C. The present invention also relates to a pharmaceutical composition containing these compounds and a method for producing the same.

Background of the invention

Hepatitis C virus (HCV) is a system of positive single-stranded RNA viruses that cause non-A, non-B hepatitis worldwide. A large proportion of patients infected with HCV have evolved into chronic liver disease. This chronic hepatitis C infection has a high risk of future death from severe liver diseases such as cirrhosis, hepatocellular carcinoma and terminal liver disease. Currently, the treatment of hepatitis C infection is by injectable interferon or pegylated interferon such as PEG-Intron. And Pegasys Or in combination with ribavirin (Ribavirin). However, these treatments can cause serious side effects such as retinopathy, thyroiditis, acute pancreatitis, and depression. Therefore, the treatment of hepatitis C requires a safe, orally available drug. The present invention satisfies the above and related needs.

Summary of invention

In one aspect, the invention relates to a compound of formula (I): Wherein: E is -COCONR ⁵ R ⁶ , -COCF ₂ CONR ⁵ R ⁶ , -COCF ₂ C(O)OR ⁵ , -COCOR ⁷ , -COCF ₂ R ⁸ , -COR ⁹ , -COCOOR ^{1 0} , -CONR ^{1 1} R ^{1 2,} or -B (oR ^{1 3)} _2, wherein ^{R 5, R 6, R 7} , R 9, R 1 0, R 1 1, R 1 2 and R ^{1 3} is each independently selected from hydrogen, An alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocycloalkyl group; and R ⁸ is a halogen, An alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocycloalkyl group, wherein the aliphatic group in E , alicyclic and aromatic groups are 1, 2 or 3 independently selected from the group consisting of hydroxyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio , amine, monosubstituted amine, disubstituted amine, alkylsulfonyl, arylsulfonyl, carboxyl, alkoxycarbonyl, alkoxycarbonyl, alkynyloxy, enaminocarbonyl, amidino, amine Selective substitution of R ^{a of a} carbonyl, halogen or cyano group, and further wherein the aromatic or aliphatic ring system in R ^a is 1, 2 or 3 substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, carboxy or carboxyalkyl; and R ⁵ and R ⁶ and R ^{1 1} And R ^{1 2} may be bonded to nitrogen to form a 5- to 7-membered ring; R ¹ is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocycloalkyl group, wherein the aliphatic, alicyclic and aromatic groups in R ¹ are independently selected from the group consisting of a hydroxyl group, an alkoxy group, Aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amine, monosubstituted amine, disubstituted amine, alkylsulfonyl, arylsulfonyl, carboxyl, alkane Selectively substituted with R ^b of an oxycarbonyl, amidino, amine carbonyl, halogen or cyano group, and further wherein the aromatic or aliphatic ring system in R ^b is independently selected from the group consisting of 1, 2 or 3, Substituents for alkoxy, halogen, haloalkyl, haloalkoxy, cyano, carboxy or carboxyalkyl groups are optionally substituted; X is -O-, -NR ^{1 4} , -S-, -SO- or -SO ₂ -; R ³ is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkane a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocycloalkyl group, wherein the aliphatic, alicyclic and aromatic groups in R ³ are 1 or 2 independently selected from hydroxy, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amine, monosubstituted amine, disubstituted Selective substitution of R ^c of an amine group, an alkylsulfonyl group, an arylsulfonyl group, a carboxyl group, an alkoxycarbonyl group, a decylamino group, an amine carbonyl group, a halogen or a cyano group, and further wherein the aromatic group in R ^c Or the aliphatic ring system is optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, carboxy or carboxyalkyl; Y is -C (O) NH-, -OC(O)NH-, NR ^{1 4} -C(O)NH- or -NR ^{1 4} C(O)O-. For each X and Y, independently selected from hydrogen when R ^{1 4} is present; halogen, hydroxy, alkoxy, amine, monosubstituted amine, disubstituted amine and aryl, heteroaryl or hetero a cyclically optionally substituted alkyl group which is optionally substituted with a halogen and an alkyl group, respectively; R ² is a heteroaryl or —CO—(fused heterocyclic) ring wherein the heteroaryl and fused heterocyclic ring The base ring is 1, 2, 3 or 4 independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, Carboxyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl, aminalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl, arylsulfonyl, arylcarbonyl, aryloxycarbonyl Aminesulfonyl, amine carbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl, heterocycloalkyl, heterocyclosulfonyl , R ^d of a heterocyclic carbonyl group, a heteroepoxycarbonyl group, an amine group, a monosubstituted amino group or a disubstituted amine group is selectively substituted, or when two R ^{d are} located adjacent to each other, they form together with the attached carbon atom. Containing 1 or 2 selected from nitrogen, , Sulfur or -SO ₂ - 4,5 of heteroatom or 6-membered heterocyclyl ring, wherein the heterocyclyl ring system is optionally substituted by 1 or 2 alkyl groups; and in addition the R ^d wherein The aromatic or alicyclic ring is independently selected from the group consisting of an alkyl group, an alkylcarbonylamino group, an alkoxycarbonylamino group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkyloxycarbonylamino group, and a ring. Alkyl alkoxycarbonylamino, nitro, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, haloalkyl, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, amine , a monosubstituted amino group, a disubstituted amine group, a guanido group or a ureido-R ^e selectively substituted, wherein the cycloalkyl and cycloalkylalkyl groups in R ^e are 1, 2 or 3 The alkyl group is optionally substituted; and R ⁴ is: (i) an alkyl group, if Y is -OC(O)NH-, NR ^{1 4} -C(O)NH- or NR ^{1 4} C(O)O- and When R ² is heteroaryl, at least one of R ^{d is} not hydrogen; (ii) cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic Or a heterocycloalkyl group, wherein the heteroaryl group and the fused heterocyclyl ring in R ² are substituted by at least one heteroaryl ring; or (iii An alkyl group, wherein when Y is -C(O)NH- or -SO ₂ NH-, the heteroaryl and fused heterocyclyl ring in R ² is substituted by at least one heteroaryl ring; wherein R ⁴ is The aromatic or alicyclic ring is 1, 2 or 3 independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, carboxy, carboxyalkyl, hydroxyalkyl, Alkoxyalkyl, aminalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl, arylsulfonyl, arylcarbonyl, aryloxycarbonyl, sulfonyl, amine carbonyl, hetero Aryl, heteroarylalkyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl, heterocycloalkyl, heterocyclosulfonyl, heterocyclic carbonyl, heteroepoxycarbonyl, The R ^{f of} the monosubstituted or disubstituted amine group is optionally substituted, wherein the aromatic or alicyclic ring in R ^f is independently selected from the group consisting of 1, 2 or 3 independently selected from the group consisting of alkyl, alkoxy, halogen, halogen The substituent of an alkyl group, a haloalkoxy group, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, a monosubstituted amino group, a disubstituted amino group or a decylamino group is optionally substituted; or a pharmaceutically acceptable salt thereof.

For the sake of clarity, the point of attachment of the Y group to the R ⁴ group has been indicated as follows: R ⁴ C(O)NH-, R ⁴ OC(O)NH-, R ⁴ NR ^{1 4} -C(O)NH- or R ⁴ NR ^{1 4} C(O)O-.

In a second aspect, the invention relates to a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a third aspect, the invention relates to a method of treating hepatitis C in an animal, the method comprising administering to the animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceuticals A pharmaceutical composition that accepts an excipient.

In a fourth aspect, the invention relates to a process for the manufacture of a compound of formula (I).

Detailed description of the preferred embodiment definition

Unless otherwise stated, the following definitions of terms used in the specification and patent application are for the purposes of this patent application and have the following meanings.

"Cycloaliphatic" means a radical having the character of configuring a carbon atom within a closed non-aromatic ring structure, such as a cycloalkyl and heterocyclyl ring as defined herein.

"Aliphatic" means an alkyl, alkenyl or alkynyl group as defined herein.

"Alkyl" by itself means, unless otherwise stated, a straight or branched saturated aliphatic radical containing from 1 to 8 carbon atoms, for example alkyl including methyl, ethyl, propyl, isopropyl, butyl. , second butyl, isobutyl, tert-butyl, and the like.

The "alkylcarbonylamino group" means a -NHC(O)R group wherein R is an alkyl group as defined above, for example, a methylcarbonylamino group, an ethylcarbonylamino group or the like.

"Alkenyl" means, unless otherwise stated, a straight or branched saturated aliphatic divalent group having from 1 to 6 carbon atoms, such as methylene (-CH ₂ -), ethylene (-CH) ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), 2-methylbutylene (-CH ₂ CH (-CH _{3 )} CH ₂ CH ₂ -), pentylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), and the like.

"Alkenyl" means a straight-chain monovalent hydroxyl group of 2 to 6 carbon atoms or a branched monovalent hydroxyl group of 3 to 6 carbon atoms having 1 or 2 double bonds, such as a vinyl group, a propenyl group (including all Isomerized), 1-methacryloyl, butenyl (including all isomeric), or pentenyl (including all isomeric), and the like.

"Alkenyloxycarbonyl" means a -C(O)OR group wherein R is an alkenyl group as defined above, for example, 3-propen-1-yloxycarbonyl and the like.

"Enamine carbonyl" means a -C(O)NHR group wherein R is an alkenyl group as defined above, for example, 3-propen-1-ylaminecarbonyl, and the like.

"Alkynyl" means a linear monovalent hydroxyl group of 2 to 6 carbon atoms or a branched monovalent hydroxyl group of 3 to 6 carbon atoms having 1 or 2 triple bonds, such as ethynyl, propynyl (including all Isomerized), 1-methylpropynyl, butynyl (including all isomeric), or pentynyl (including all isomeric), and the like.

"Alkynyloxycarbonyl" means a -C(O)OR group wherein R is an alkynyl group as defined above, for example, 3-propyn-1-yloxycarbonyl and the like.

"Alkylthio" means an -SR group wherein R is an alkyl group as defined herein, for example, methylthio, ethylthio, propylthio, or butylthio, and the like.

"Alkylsulfonyl group" means a group -SO ₂ R wherein R is alkyl as defined herein, acyl e.g. methanesulfonic, ethanesulfonic acyl and the like.

"Alkoxy" means an -OR group wherein R is alkyl as defined herein, for example methoxy, ethoxy, and the like.

"Alkoxycarbonylamino" means an -NHC(O)OR group wherein R is alkyl as defined herein, for example methoxycarbonylamino, ethoxycarbonylamino and the like.

"Alkoxyalkyl" means a straight-chain monovalent hydroxy group of 1 to 6 carbon atoms or substituted with at least one alkoxy group as defined above, preferably 1 or 2 alkoxy groups, substituted for 3 to 6 carbons A branched monovalent hydroxyl group of an atom, such as 2-methoxyethyl; 1-, 2- or 3-methoxypropyl; 2-ethoxyethyl, and the like.

"Amine" means an -NH ₂ group.

"Alkylamino" means an -NHR group whose R is an alkyl group as defined herein, such as methylamino; ethylamino; n-, i-propylamino; n-, iso-, tert-butylamino, etc. .

"Amine alkyl" means a linear monovalent hydroxyl group of 1 to 6 carbon atoms or a branched monovalent hydroxyl group substituted by at least 1 -NRR', preferably 1 or 2, substituted 3 to 6 carbon atoms. , R is hydrogen, alkyl, decyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl as defined herein and R' is hydrogen , alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, cycloalkylalkyl, amine carbonyl or amine sulfonium sulfonate The group is, for example, an aminomethyl group, a methylaminoethyl group, a dimethylaminoethyl group, a 1,3-diaminopropyl group, an acetaminopropyl group or the like.

"Amidino" means a -COR group wherein R is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocyclyl as defined herein, For example, methyl ketone, ethyl sulfonyl, trifluoroethyl fluorenyl, benzhydryl, and piperazine -1-ylcarbonyl and the like. When R is an alkyl group it is referred to herein as an alkylcarbonyl group. When R is an aryl group it is referred to herein as an arylcarbonyl group. When R is a heteroaryl group it is referred to herein as a heteroarylcarbonyl group. When R is a heterocyclic group, it is referred to herein as a heterocyclic carbonyl group.

"Amidino" means that R is hydrogen or alkyl as defined herein and R' is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or a -NRCOR' group of a heterocyclic group, such as a methyl group, an ethyl group, a trifluoroethyl group, a benzamidine group, a piperidine group -1-ylcarbonyl and the like.

"Aminecarbonyl" means that R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, as defined herein, or R and R, A -CONRR' group which forms a heterocyclic amine group together with a nitrogen atom.

"Aminesulfonyl" means that R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl as defined herein, or R and R' together with a nitrogen atom to form a -SO ₂ NRR' group of a heterocyclic amine group.

"Animals" include humans, non-human mammals (eg, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.) and non-mammals (eg, birds, etc.).

"Aromatic" means a moiety in which the constituent atoms constitute an unsaturated ring system, all of the atomic systems in the ring system are sp ² bonded and the total number of pi electrons is equal to 4n+2.

"Aryl" means a monocyclic or fused bicyclic combination of 6 to 10 cyclic carbon atoms in which each ring is aromatic, such as phenyl or naphthyl.

"Aryloxy" means an -O-R group wherein R is an aryl group as defined above, for example, phenoxy, naphthyloxy and the like.

"Alkoxycarbonyl" means a -C(O)OR group wherein R is an aryl group as defined above, for example, phenoxycarbonyl, naphthyloxycarbonyl and the like.

"Aralkyl" means an -(enyl)-R group wherein R is aryl as defined above, for example benzyl, phenethyl and the like.

"Arylthio" means an -SR group wherein R is aryl as defined herein, for example phenylthio or naphthylthio.

"Arylsulfonyl" means an -SO ₂ R group wherein R is an aryl group as defined herein, for example, phenylsulfonyl or naphthylsulfonyl.

"Carboxy" refers to a -C(O)OH group.

"Carboxyalkyl" means an alkyl group substituted with at least one -C(O)OH group, preferably 1 or 2, as defined herein, for example carboxymethyl; carboxyethyl; 1-, 2 - or 3-carboxypropyl and the like.

"Cycloalkyl" means a monovalent saturated monocyclic ring containing from 3 to 8 cyclic carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

"Cycloalkylalkyl" means an -(enyl)-R group wherein R is a cycloalkyl group as defined above, such as cyclopropylmethyl, cyclobutylethyl, cyclobutylmethyl and the like.

"Cycloalkoxy" means an -OR group wherein R is a cycloalkyl group as defined above, for example, cyclopropoxy, cyclopentyloxy, cyclohexyloxy and the like.

The "cycloalkoxycarbonylamino group" means an -NHC(O)OR group wherein R is a cycloalkyl group as defined above, for example, a cyclopropoxycarbonylamino group, a cyclopentyloxycarbonylamino group or the like.

"Cycloalkylalkoxycarbonylamino" means a -NHC(O)OR group wherein R is a cycloalkylalkyl group as defined above, for example cyclopropylmethoxycarbonylamino, cyclopentylmethoxycarbonylamine Base.

"Disease" specifically includes any unhealthy state of an animal or part thereof and the unhealthy state resulting from or accompanying the veterinary treatment of the drug or animal, ie the "side effects" of such treatment.

"Disubstituted amino" means that R and R' are independently selected from alkyl, cycloalkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aminalkyl, aryl, as defined herein, a -NRR' group of an aralkyl, heteroaryl or heteroarylalkyl group, such as dimethylamino, diethylamino, N,N-propylamino or N,N-methylethylamino, methylanilino Wait. A subgroup of dialkylamino based disubstituted amine groups.

"Fused heterocyclyl" means a heterocyclic group fused to an aryl or heteroaryl ring as defined herein, eg, 2,3-dihydroisoindol-1-yl, 1,2,3,4- Tetrahydroisoquinolin-1-yl and the like.

"Halogen" means fluoro, chloro, bromo or iodo.

"Haloalkyl" means an alkyl radical as defined above which is substituted by one or more "halogen" atoms as defined in this application, preferably from 1 to 7. Haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like, such as chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2 -Trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like.

"Haloalkoxy" means an -OR group wherein R is a haloalkyl group as defined above, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, and the like.

"Heteroaryl" is a group or a partial group having an aromatic monocyclic or bicyclic moiety of 5 to 10 carbon atoms, and one or more ring atoms, preferably 1, 2 or 3, are selected from Nitrogen, oxygen or sulfur, the remaining ring atoms are carbon. Representative heteroaryl rings include, but are not limited to, pyrrolyl, furyl, thienyl, Oxazolyl, different Azolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridyl Pyrazinyl Pyridazinyl, fluorenyl, benzofuranyl, benzophenylthio, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinacrid Quinoxalinyl, pyrazolyl and the like.

"Heteroaryloxy" means an -O-R group wherein R is a heteroaryl group as defined above, for example, furanyloxy, pyridinyloxy, indolyloxy, and the like.

"Heteroalkoxycarbonyl" means a -C(O)O-R group wherein R is a heteroaryl group as defined above, for example, piperidinyloxycarbonyl, pyrimidinyloxycarbonyl or the like.

"Heteroaralkyl" means an -(enyl)-R group wherein R is a heteroaryl group as defined above, for example, piperidinylmethyl, 1- or 2-furanethyl, imidazolylmethyl and the like.

"Heteroaralkyloxycarbonyl" means a -C(O)O-R group wherein R is a heteroaralkyl group as defined above, for example, piperidine methoxycarbonyl, pyrimidine methoxycarbonyl, and the like.

"Heteroarylthio" means an -SR group wherein R is a heteroaryl group as defined herein, such as piperidinylthio, furylthio, thiophenothionyl and the like.

"Heteroaryl sulfo acyl" means wherein R is a -SO ₂ R radical where heteroaryl is defined, such as piperidine sulfonic acyl, acyl thiophenesulfonamide like.

"Heterocyclyl" means a saturated or partially unsaturated, mono or bicyclic group of 4, 5, 6 or 7 carbon ring atoms, wherein one or more ring carbon atoms, preferably 1, 2 or 3, are Substituted by a hetero atom selected from -N=, -N-, -O-, -S-, -SO- or -S(O) ₂ - and further wherein one or two of the ring carbon atoms are replaced by a ketone (-CO- The base is selectively substituted. The heterocyclyl ring is selectively fused to a cycloalkyl, aryl or heteroaryl ring as defined herein. Representative examples include, but are not limited to, imidazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1-oxide, thiomorpholine-1,1-di Oxide, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetrathiopyranyl, dihydrogen Indolinyl, piperazine Piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, 3,4-dihydroisoquinolinyl, indanyl, etc. . When the heterocyclic group contains at least one nitrogen ring atom, it is referred to herein as "heterocyclic amine group" and it is a subset of the above-defined heterocyclic group.

"Heterocycloalkyl" means an -(enyl)-R group wherein R is a heterocyclic group as defined above, for example, pyrrolidinylmethyl, tetrahydrofuranethyl, pyridinemethylpiperidinemethyl and the like.

The "heterocyclic carbonyl group" means a -C(O)O-R group wherein R is a heterocyclic group as defined above, for example, piperidinyloxycarbonyl, tetrahydrofuranoxycarbonyl or the like.

"Heterocyclic sulfonyl" means a -SO ₂ R group wherein R is a heterocyclic group as defined herein, for example, piperidin-1-ylsulfonyl, pyrrolidin-1-ylsulfonyl and the like.

"Hydroxy" means an -OH group.

"Hydroxyalkyl" means a linear monovalent hydroxyl group of 1 to 6 carbon atoms or a branched monovalent hydroxyl group of 3 to 6 carbon atoms substituted by 1 or 2 hydroxyl groups, but if two hydroxyl groups are simultaneously present Non-position on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2 -hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3 , 4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2- Hydroxyethyl.

"Isomer" means a compound of formula (I) having the same molecular formula but different atom bonding properties or order or atomic space configuration. Isomers whose atoms have different spatial configurations are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "non-image isomers" and stereoisomers that are not superimposable mirror images are referred to as "mirroromers" or sometimes "optical isomers". A carbon atom bonded to four non-identical substituents is referred to as "center to palm". A pair of mirror-isomeric compounds with opposite palmar centers in the center of the palm are referred to as "racemic mixtures." Having more than one compound having a charge of 2 ^{n -} centered on ^Spiegelmers which n is the number of the center of the palm. More than one palm-centered compound may have a single non-image isomer or a mixture of non-image isomers known as "non-mirrored mixtures." When a stereoisomer exists in the center of a pair of palms, it can be characterized by the absolute configuration of the center of the palm. Absolute configuration refers to the spatial configuration of the substituents attached to the center of the palm. It is characterized by its absolute configuration of the absolute configuration of the center of the palm and by the R- and S-sorting rules of Cahn, Ingold and Prelog. Stereochemical naming conventions, methods for determining stereochemistry, and separation methods for stereoisomers are well known in the art (for example, see "Advanced Organic Chemistry" Fourth Edition, April, Jrry, John Wiley, and Sons, New York. , 1992). It is understood that the names and descriptions used to describe the compounds of formula (I) in this application should include all possible stereoisomers.

"monosubstituted amine group" means that R is selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminalkyl, aryl, aralkyl, as defined herein. A -NHR group of a heteroaryl or heteroarylalkyl group, such as methylamino, ethylamino, propylamino, anilino, benzylamino and the like.

"Selected" or "optionally" or "may be" means that a subsequent description event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurred and the instance did not occur. For example, the phrase "wherein the aromatic ring in R ^a is optionally substituted with 1 or 2 substituents independently selected from alkyl" means that the aromatic ring may or may not be substituted by an alkyl group and may conform to the present invention. In the range.

The invention also includes N -oxidized derivatives of the compounds of formula (I). The N -oxidized derivative means a compound of the formula (I) whose nitrogen atom is in an oxidized state (i.e., N ? O), for example, an N -oxidized pyridine having a desired pharmacological activity.

The "pathology" of a disease means the underlying nature, cause and development of the disease and the structural and functional changes resulting from the disease process.

"Pharmaceutically acceptable" means effective use in the manufacture of a pharmaceutical composition which is generally safe, non-toxic, non-biological or otherwise undesirable for veterinary use and human medical use.

"Pharmaceutically acceptable salt" means a salt of a compound of formula (I) which is pharmaceutically acceptable and has the desired pharmacological activity as defined above. Such salts include acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed from organic acids such as acetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentane Propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzidine) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzene Sulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]oct-2-ene-1-carboxylic acid, glucoheptonic acid ), 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, dimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, Glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic, and the like.

Pharmaceutically acceptable salts also include base addition salts which form acidic proteins which are reactive with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N -methylglucamine, and the like.

The invention also includes prodrugs of the compounds of formula (I). Prodrug means a compound which can be converted to a compound of formula (I) by metabolic means (i.e., by hydrolysis) in vivo. For example, an ester of a compound of formula (I) containing a hydroxy group can be converted to its parent molecule by hydrolysis in vivo. Alternatively, an ester of a compound of formula (I) containing a carboxy group can be converted to its parent molecule by hydrolysis in vivo. Suitable esters of the compound of formula (I) containing a hydroxyl group are, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, anti Butenediates, maleic acid esters, methylene bis-β b-hydroxynaphthoate, gentisates, isethionates, bis-p-tolylmethyl Tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of the compound of formula (I) containing a carboxy group are described, for example, in Leinweber, FJ Drug Metab . Res ., 1987, 18 , page 379. Particularly effective esters of the compound of formula (I) containing a hydroxy group can be formed from an acid group selected from the group consisting of Bundgaard et al., J. Med. Chem. , 1989, 32, pages 2503 to 2507, and including a substitution (amine A). a benzoic acid ester such as a dialkylaminomethyl benzoate wherein the two alkyl groups are linked to each other and/or are separated by an oxygen atom or a selectively substituted nitrogen atom such as an alkylated nitrogen atom, more particularly Refers to (morpholinyl)benzoic acid such as 3- or 4-(morpholinyl)benzoic acid and (4-alkylpiperidine) -1-yl)benzoic acid such as 3- or 4-(4-alkylpiperidine -1-yl)benzoic acid. It is understood that the names and descriptions used to describe the compounds of formula (I) in this application should include all possible prodrugs thereof.

"Protected derivative" means a derivative of a compound of formula (I) which is blocked by a protecting group at its reaction site. A protected derivative of a compound of formula (I) can be used effectively to produce a compound of formula (I) or itself can be an active cell autolysin S (cathepsin S) inhibitor. A list of suitable protecting groups can be found in TW Greene's Organic Synthesis Protection Group, Third Edition, John Wiley and Sons, 1999. It is understood that the names and descriptions of the compounds of formula (I) used in the present application should include all possible protected derivatives thereof.

"Therapeutically effective dose" means a dose sufficient to produce a therapeutic effect on a disease when administered to an animal for the treatment of a disease.

"Treatment" or "treatment" means any administration of a compound of the invention and includes: (1) a disease that prevents the animal from developing an onset but still does not feel or present a path or symptom of the disease; (2) inhibiting the animal from feeling or presenting a disease or pathological condition of the disease (ie, preventing further progression of pathology and/or symptomology); or (3) a disease that alleviates the pathology or symptoms of the disease that the animal has felt or presents (ie, reverses the pathology and/or symptoms) The phenomenon).

"ureido" means a -NHCONRR' group wherein R is hydrogen or alkyl and R' is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl.

Certain compounds of formula (I) which are more preferred within the abstract of the invention are described in the broadest sense. For example: A. The following are preferred groups for the compounds of formula (I) wherein: E is -COCONHR ⁶ , and R ⁶ is hydrogen, alkyl, cycloalkyl, aralkyl or heteroarylalkyl, wherein the aromatic ring Optionally substituted by 1 or 2 halogens, R ^{6 is} preferably cyclopropyl, -CH(CH ₃ )R, R is phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2, 4-difluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl or pyridin-4-yl. R ^{6 is} preferably a cyclopropyl group.

B. The following is another preferred group of compounds of formula (I) wherein: E is -COCOOR ^{1 0} , and R ^{1 0} is a definition within the abstract of the invention. R ^{1 0 is} preferably -CH ₂ C≡CH, -CH ₂ CH=CH ₂ , n-propyl, 2,2-dimethylpropyl, carboxymethyl, methoxycarbonylmethyl, tert-butoxycarbonyl Methyl, -CH ₂ C(O)OCH ₂ C ≡ CH, -CH ₂ C(O)OCH ₂ CH=CH ₂ , -CH ₂ C(O)O(CH ₂ ) ₂ CH ₃ , -CH ₂ C (O)NH ₂ , -CH ₂ C(O)NHCH ₃ , -CH ₂ C(O)N(CH ₃ ) ₂ , -CH ₂ C(O)NHCH ₂ CH=CH ₂ or ₂ -phenylethyl.

(a) In the above preferred groups of A and B and the preferred groups thereof, the following are more preferred compounds, wherein: X is -O-; R ¹ is alkoxy, alkylthio or alkane Alkylsulfonyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl optionally substituted alkyl, preferably methyl, ethyl, n-propyl, n-butyl, n-pentyl, propyl- 2-alkenyl, propyn-2-yl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, methoxymethyl, 2 - methoxyethyl, methylthiomethyl, methylsulfonylmethyl or cyclobutylmethyl. More preferably, it is a cyclobutylmethyl group, an ethyl group, a n-propyl group or a n-butyl group; and R ³ is an alkyl group, a cycloalkyl group or an aryl group, more preferably 1-methylethyl group, 1-methylpropyl group, Tributyl, cyclopropyl, phenyl or cyclohexyl. R ^{3 is} preferably a tributyl or cyclohexyl group.

(1) Among the groups (A), (B), A(a) and B(a) and the more preferred groups thereof, the following are preferred groups of the compound, wherein: Y is -OC(O)NH- ; R ² is 1, 2, 3 or 4 independently selected from hydrogen, aryl, cycloalkyl, alkynyl, alkylthio, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, carboxy , carboxyalkyl, hydroxyalkyl, alkoxyalkyl, aminalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl, arylsulfonyl, arylcarbonyl, aryloxycarbonyl, Aminesulfonyl, amine carbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl, heterocycloalkyl, heterocyclosulfonyl, a heteroaryl group optionally substituted by R ^d of a heterocyclic carbonyl group, a hetero epoxycarbonyl group, an amine group, a monosubstituted amino group or a disubstituted amine group, or a bonded carbon when two R ^{d are} located adjacent to each other The atoms together form a 4, 5 or 6-membered heterocyclyl ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen, sulfur or -SO ₂ - wherein the heterocyclyl ring is 1 or 2 alkyl the optionally substituted; and in addition the aromatic or alicyclic ring in which R ^d is independently 1, 2 or 3 From alkyl, alkoxycarbonylamino, cycloalkyl, cycloalkylalkyl, cycloalkyloxycarbonylamino, cycloalkylalkoxycarbonylamino, nitro, alkoxy, cycloalkoxy, aryloxy Selective substitution of R ^e of a group, a heteroaryloxy group, a halogen, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, an amine group, a disubstituted amine group, a decylamino group or a ureido group, wherein R The cycloalkyl and cycloalkylalkyl groups in ^e are optionally substituted with 1, 2 or 3 alkyl groups; and R ⁴ is an alkyl group, preferably a third butyl methyl group but at least one R ^{d is} not hydrogen.

(i) R ^{2 is} preferably a group of formula (a): Wherein: R ^{d 1} is hydrogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy or alkylsulfonyl; R ^d and R ^{d 2} are independent hydrogen, alkyl , halogen, alkoxy, alkylthio or alkylsulfonyl; or R ^{d 1} and R ^d or R ^{d 1} and R ^{d 2} together with a carbon atom to form a heterocyclic group of 4, 5, or 6 atoms a ring in which one or two ring atoms are optionally substituted by oxygen or -N-, wherein the heterocyclic ring is optionally substituted by 1 or 2 alkyl groups; R ^{d 3} is halogen, alkyl, cycloalkyl or cycloalkyl Alkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino, alkoxycarbonylamino, amine, alkylamino, An aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by a dialkylamino, cycloalkylamino, cycloalkylalkylamino or -NHCONRR', wherein R is hydrogen or alkyl and R' It is a hydrogen, alkyl, cycloalkyl or cycloalkylalkyl group in which a cycloalkyl group and a cycloalkylalkyl group in R ^{d 3} are selectively substituted by 1, 2 or 3 alkyl groups.

Preferably, R ^{d 1} is hydrogen, hydroxy, alkoxy, amine, alkylamino or dialkylamino; R ^d and R ^{d 2} are independently hydrogen, alkyl, halogen, alkoxy, alkane sulphur Or an alkylsulfonyl group; and R ^{d 3} is a group of the formula: By halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino, Alkenically substituted with alkoxycarbonylamino, amine, alkylamino, dialkylamino, cycloalkylamino, cycloalkylalkylamino or -NHCONRR', wherein R is hydrogen or alkyl and R' is Hydrogen, alkyl, cycloalkyl or cycloalkylalkyl wherein cycloalkyl and cycloalkylalkyl are optionally substituted with 1, 2 or 3 alkyl groups.

R ^{d 3 is more} preferably the basis of the following formula: By halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino, Alkenically substituted with alkoxycarbonylamino, amine, alkylamino, dialkylamino, cycloalkylamino, cycloalkylalkylamino or -NHCONRR', wherein R is hydrogen or alkyl and R' is Hydrogen, alkyl, cycloalkyl or cycloalkylalkyl wherein cycloalkyl and cycloalkylalkyl are optionally substituted with 1, 2 or 3 alkyl groups.

R ^{d 3} is more preferably the basis of the following formula: By halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino, Alkenically substituted with alkoxycarbonylamino, amine, alkylamino, dialkylamino, cycloalkylamino, cycloalkylalkylamino or -NHCONRR', wherein R is hydrogen or alkyl and R' is Hydrogen, alkyl, cycloalkyl or cycloalkylalkyl wherein cycloalkyl and cycloalkylalkyl are optionally substituted with 1, 2 or 3 alkyl groups.

In still other preferred embodiments of subgroup (i), R ^{d 3} is a cycloalkyl group, more preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group, still more preferably a cyclopropyl group. The remaining groups R ^d , R ^{d 1} and R ^{d 2} have the meanings described for the formula (a).

In the above preferred groups, the following are more preferred groups of the compound, wherein: R ^{d 1} is hydrogen, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino , n-propylamino, isopropylamino, dimethylamino, methyl ethylamino, methyl (n-propyl) amine and methyl (isopropyl) amine; more preferably hydrogen, hydroxyl, methoxy Or a dimethylamino group, more preferably a methoxy group. Alternatively, it is more preferably hydrogen; R ^d and R ^{d 2} are independently hydrogen, fluorine, chlorine, methyl, ethynyl, methoxy, ethoxy, methylthio or methylsulfonyl. R ^{d is more} preferably hydrogen, ethynyl, fluorine, chlorine, methyl, methoxy, methylthio or methylsulfonyl and R ^{d 2} is hydrogen.

R ^{d 1 is} most preferably methoxy, R ^d is hydrogen or methyl, fluorine, chlorine or methoxy and R ^{d 2} is hydrogen.

(ii) R ^{2 is} preferably a base of the formula: Wherein: Z _a and Z _b is independently -O- or -NH-, which H may be substituted with R, Z _a and Z _b is preferably -O-; R & lt alkyl group, preferably methyl; R ^{d 2} is hydrogen or methyl, preferably hydrogen; and R ^{d 3} is the definition of the above subgroup (i).

(iii) R ^{2 is} preferably a base of the formula: Z _a and Z _b are independently -O- or -NH-, H may be substituted by R, Z _a and Z _{b are} preferably -O-; R is an alkyl group, preferably a methyl group; R ^{d 2} is Hydrogen or methyl, preferably hydrogen; and R ^{d 3} is the definition of the immediately preceding subgroup (i).

(iv) R ^{2 is} preferably a group of formula (b): Wherein: R ^{d 1} is hydrogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy or alkylsulfonyl; R ^d and R ^{d 2} are independent hydrogen, alkyl , halogen, alkoxy, alkylthio or alkylsulfonyl; or R ^{d 1} and R ^d or R ^{d 1} and R ^{d 2} together with a carbon atom to form a heterocyclic group of 4, 5, or 6 atoms a ring in which one or two ring atoms are optionally substituted by oxygen or -N-, wherein the heterocyclic ring is optionally substituted by 1 or 2 alkyl groups; R ^{d 3} is hydrogen, alkyl, cycloalkyl or cycloalkyl base.

Preferably, R ^{d 1} is hydrogen, hydroxy, alkoxy, amine, alkylamino or dialkylamino; R ^d and R ^{d 2} are independently hydrogen, alkyl, halogen, alkoxy, alkane sulphur Or alkylsulfonyl; and R ^{d 3} is hydrogen, alkyl or cycloalkyl.

In the above preferred groups, the following are more preferred groups of the compound, wherein: R ^{d 1} is hydrogen, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino , n-propylamino, isopropylamino, dimethylamino, methyl ethylamino, methyl (n-propyl) amine and methyl (isopropyl) amine; more preferably hydrogen, hydroxyl, methoxy a ethoxy or dimethylamino group, more preferably a methoxy or ethoxy group; and R ^d and R ^{d 2} are independently hydrogen, fluorine, chlorine, methyl, ethynyl, methoxy, Oxy, methylthio or methylsulfonyl; R ^{d is more} preferably hydrogen, ethynyl, fluoro, chloro, methyl, methoxy, methylthio or methylsulfonyl and R ^{d 2} is hydrogen.

R ^{d 1 is} most preferably methoxy or ethoxy, R ^d is hydrogen or methyl, fluorine, chlorine or methoxy and R ^{d 2} is hydrogen.

In the above groups (i) to (iii) and the more preferred groups thereof, a more preferred group of the compounds is wherein the R ^{d 3} ring is methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, 2,2,-dimethylpropyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropane Selectively substituted by a group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group and a cyclohexylmethyl group, each of the cycloalkyl groups and rings The alkylalkyl ring is optionally substituted with from 1 to 3 substituents independently selected from methyl or ethyl, preferably methyl.

In the above groups (i) to (iii) and more preferred groups thereof, a more preferred group of the compounds is wherein the R ^{d 3} ring is bonded to an amine group, a methylamino group, an ethylamino group, an propylamino group or a 1-methyl group. Ethylamino, 1,1-dimethylethylamino, 2-methylpropylamino, 1-methylpropylamino, 2,2-dimethylpropylamino, 1,2 - dimethylpropylamino, 1,1-dimethylpropylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamine , cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, 1-methylethylamino, 1, 1-Dimethylethylamino group, 2-methylpropylamino group, 1-methylpropylamino group, 2,2-dimethylaminocarbonyl group, 1,2-dimethylaminocarbonyl group, 1,1- Dimethyl propylaminocarbonyl, cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, cyclopropylaminocarbonyl, butylated methylamino, cyclopentam Carboaminocyclohexylcarbonylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamine, 1-methylethoxycarbonylamino, 1,1-di -Ethoxycarbonylamino, 2-propoxycarbonylamino, 1-propoxycarbonylamino, 2,2-dimethylpropoxycarbonyl, 1,2-dimethylpropoxycarbonylamino or 1,1-Dimethylpropoxycarbonylamino group is optionally substituted.

(2) Among the groups (A), (B), A(a) and B(a) and the more preferred groups thereof, the following are preferred groups of the compound, wherein: Y is -NHC(O)NH- R ² is a definition of the above preferred embodiment (1), including a preferred subgroup thereof, and R ⁴ is an alkyl group, preferably a third butyl group.

(3) Among the groups (A), (B), A(a) and B(a) and the more preferred groups thereof, the following are preferred groups of the compound, wherein: Y is -C(O)NH- R ² is a definition of the above preferred embodiment (1), and if R ^{d 3} is a heteroaryl ring, a preferred subgroup thereof is included, and R ⁴ is a definition in the abstract, preferably an alkyl group. More preferably, it is a third butyl group.

(4) Among the groups (A), (B), A(a) and B(a) and the more preferred groups thereof, the following are more preferred groups of compounds, wherein: Y is -OC(O)NH- , R ² is -CO-(fused heterocyclic group), wherein the fused heterocyclic ring is 1, 2 or 3 independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, carboxy, Carboxyalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl, arylsulfonyl, arylcarbonyl, alkoxycarbonyl, amine sulfonate Mercapto, amine carbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl, heterocycloalkyl, heterocyclosulfonyl, heterocycle a carbonyl group, a heterocyclic oxycarbonyl group, a substituted amino group mono or di-substituted amino group optionally substituted by R ^d, wherein the aromatic or alicyclic ring in R ^d is 1, 2 or 3 substituents independently selected from alkyl, alkoxy alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, mono-substituted amino, di-substituted amino or acyl group optionally substituted by a R ^e; and R ⁴ is alkyl. R ^{2 is} preferably 2,3-dihydroisoindol-1-yl, 1,2,3,4-tetrahydroisoquinoline-1 substituted by 1, 2 or 3 immediately followed by R ^d . -base.

(5) Among the groups (A), (B), A(a) and B(a) and the more preferred groups thereof, the following are preferred groups of the compound, wherein: Y is -NHC(O)NH- , R ² is -CO-(fused heterocyclic group), wherein the fused heterocyclic ring is 1, 2 or 3 independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, carboxy, Carboxyalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl, arylsulfonyl, arylcarbonyl, alkoxycarbonyl, amine sulfonate Mercapto, amine carbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl, heterocycloalkyl, heterocyclosulfonyl, heterocycle a carbonyl group, a heterocyclic oxycarbonyl group, a substituted amino group mono or di-substituted amino group optionally substituted by R ^d, wherein the aromatic or alicyclic ring in R ^d is 1, 2 or 3 substituents independently selected from alkyl, alkoxy alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, mono-substituted amino, di-substituted amino or acyl group optionally substituted by a R ^e; and R ⁴ is alkyl. R ^{2 is} preferably 2,3-dihydroisoindol-1-yl, 1,2,3,4-tetrahydroisoquinoline selectively substituted by 1, 2 or 3 immediately adjacent to R ^d -1- base.

C. The following is still another preferred group of compounds of formula (I) wherein R ² is a group of formula (a): Wherein: R ^{d 1} is hydrogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy or alkylsulfonyl; R ^d and R ^{d 2} are independent hydrogen, alkyl , halogen, alkoxy, alkylthio or alkylsulfonyl; or R ^{d 1} and R ^d or R ^{d 1} and R ^{d 2} together with a carbon atom to form a heterocyclic group of 4, 5, or 6 atoms a ring in which one or two ring atoms are optionally substituted by oxygen or -N-, wherein the heterocyclic ring is optionally substituted by 1 or 2 alkyl groups; R ^{d 3} is halogen, alkyl, cycloalkyl or cycloalkyl Alkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino, alkoxycarbonylamino, amine, alkylamino, An aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by a dialkylamino group or -NHCONRR', wherein R is hydrogen or alkyl and R' is hydrogen, alkyl, cycloalkyl or naphthenic An alkyl group in which a cycloalkyl group and a cycloalkylalkyl group are selectively substituted by 1, 2 or 3 alkyl groups.

(i) Preferably, R ^{d 1} is hydrogen, hydroxy, alkoxy, amine, alkylamino or dialkylamino; R ^d and R ^{d 2} are independently hydrogen, alkyl, halogen, alkoxy , alkylthio or alkylsulfonyl; and R ^{d 3} is a group of the formula: By halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino, Alkenically substituted with alkoxycarbonylamino, amino, alkylamino, dialkylamino or -NHCONRR', R is hydrogen or alkyl and R' is hydrogen, alkyl, cycloalkyl or cycloalkyl a group wherein a cycloalkyl group and a cycloalkylalkyl group are optionally substituted with 1, 2 or 3 alkyl groups.

R ^{d 3 is more} preferably the basis of the following formula: By halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino, Alkenically substituted with alkoxycarbonylamino, amino, alkylamino, dialkylamino or -NHCONRR', R is hydrogen or alkyl and R' is hydrogen, alkyl, cycloalkyl or cycloalkyl a group wherein a cycloalkyl group and a cycloalkylalkyl group are optionally substituted with 1, 2 or 3 alkyl groups.

R ^d3 is better as the basis of the following formula: By halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino, Alkenically substituted with alkoxycarbonylamino, amino, alkylamino, dialkylamino or -NHCONRR', R is hydrogen or alkyl and R' is hydrogen, alkyl, cycloalkyl or cycloalkyl a group wherein a cycloalkyl group and a cycloalkylalkyl group are optionally substituted with 1, 2 or 3 alkyl groups.

In the above preferred groups, the following are more preferred groups of the compound, wherein: R ^d1 is hydrogen, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, N-propylamino, isopropylamino, dimethylamino, methylethylamino, methyl(n-propyl)amine and methyl(isopropyl)amine; more preferably hydrogen, hydroxy or methoxy Or a dimethylamino group, more preferably a methoxy group. Alternatively, it is more preferably hydrogen; R ^d and R ^d2 are independently hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methylthio or methylsulfonyl. R ^{d is more} preferably hydrogen, ethyl, fluorine, chlorine, methyl, methoxy, methylthio or methylsulfonyl and R ^d2 is hydrogen.

R ^{d 1 is} most preferably methoxy, R ^d is hydrogen or methyl, fluorine, chlorine or methoxy and R ^{d 2} is hydrogen.

(i) R ^{2 is} preferably a base of the formula: Wherein: Z _a and Z _b is independently -O- or -NH-, which H may be substituted with R, Z _a and Z _b is preferably -O-; R & lt alkyl group, preferably methyl; R ^{d 2} is hydrogen or methyl, preferably hydrogen; and R ^{d 3} is the definition of the above subgroup (i).

(ii) R ^{2 is} preferably a base of the formula:

Z _a and Z _b are independently -O- or -NH-, H may be substituted by R, Z _a and Z _{b are} preferably -O-; R is an alkyl group, preferably a methyl group; R ^{d 2} is Hydrogen or methyl, preferably hydrogen; and R ^{d 3} is the definition of subgroup (i) above.

In the above groups (i) to (iii) and the more preferred groups thereof, a more preferred group of the compounds is wherein the R ^{d 3} ring is methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, 2,2,-dimethylpropyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropane Selectively substituted by a group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group and a cyclohexylmethyl group, each of the cycloalkyl groups and rings The alkylalkyl ring is optionally substituted with from 1 to 3 substituents independently selected from methyl or ethyl, preferably methyl.

In the above groups (i) to (iii) and more preferred groups thereof, a more preferred group of the compounds is wherein the R ^{d 3} ring is bonded to an amine group, a methylamino group, an ethylamino group, an propylamino group or a 1-methyl group. Ethylamino, 1,1-dimethylethylamino, 2-methylpropylamino, 1-methylpropylamino, 2,2-dimethylpropylamino, 1,2 - dimethylpropylamino, 1,1-dimethylpropylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamine , cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, 1-methylethylamino, 1, 1-Dimethylethylamino group, 2-methylpropylamino group, 1-methylpropylamino group, 2,2-dimethylaminocarbonyl group, 1,2-dimethylaminocarbonyl group, 1,1- Dimethyl propylaminocarbonyl, cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, cyclopropylaminocarbonyl, butylated methylamino, cyclopentam Carboaminocyclohexylcarbonylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamine, 1-methylethoxycarbonylamino, 1,1-di -Ethoxycarbonylamino, 2-propoxycarbonylamino, 1-propoxycarbonylamino, 2,2-dimethylpropoxycarbonyl, 1,2-dimethylpropoxycarbonylamino or 1,1-Dimethylpropoxycarbonylamino group is optionally substituted.

(1) In the above preferred group of C and a more preferred group thereof, the following are more preferred compounds, wherein: X is -O-; R ¹ is alkoxy, alkylthio or alkyl An alkyl group optionally substituted with a sulfonyl, alkenyl, alkynyl or cycloalkylalkyl group, preferably an alkyl group or a cycloalkylalkyl group, preferably a methyl group, an ethyl group, a n-propyl group or a n-butyl group. , n-pentyl, prop-2-enyl, propyn-2-yl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl Base, methoxymethyl, 2-methoxyethyl, methylthiomethyl, methylsulfonylmethyl or cyclobutylmethyl. More preferably cyclobutylmethyl, ethyl or n-butyl; and R ³ is an alkyl group, an aryl group or cycloalkyl group, preferably 1-methylethyl, 1-methylpropyl, tert-butyl, Cyclopropyl, phenyl or cyclohexyl. R ^{3 is} preferably a tributyl or cyclohexyl group.

(a) In the groups C and C(1) and the more preferred groups thereof, the following are preferred groups of the compounds, wherein: E is -COCONHR ⁶ , and R ⁶ is hydrogen, alkyl, cycloalkyl, aryl An alkyl or heteroarylalkyl group, wherein the aromatic ring is optionally substituted by 1 or 2 halogens, R ^{6 is} preferably cyclopropyl, -CH(CH ₃ )R, R is phenyl, 4-chlorophenyl 2,4-Dichlorophenyl, 2,4-difluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl or pyridin-4-yl. R ^{6 is} preferably a cyclopropyl group.

(b) In the groups C and C(1) and the more preferred groups thereof, the following are preferred groups of the compounds, wherein: E is -COCOOR ^{1 0} , and R ^{1 0} is a definition within the abstract of the present invention. R ^{1 0 is} preferably -CH ₂ C≡CH, -CH ₂ CH=CH ₂ , n-propyl, 2,2-dimethylpropyl, carboxymethyl, methoxycarbonylmethyl, tert-butoxycarbonyl Methyl, -CH ₂ C(O)OCH ₂ C≡CH, -CH ₂ C(O)OCH ₂ CH=CH ₂ , -CH ₂ C(O)O(CH ₂ ) ₂ CH ₃ , -CH ₂ C (O)NH ₂ , -CH ₂ C(O)NHCH ₃ , -CH ₂ C(O)N(CH ₃ ) ₂ , -CH ₂ C(O)NHCH ₂ CH=CH ₂ or 2-phenylethyl. D. The following is still another preferred group of compounds of formula (I) wherein R ² is a group of formula (b): Wherein: R ^{d 1} is hydrogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy or alkylsulfonyl; R ^d and R ^{d 2} are independent hydrogen, alkyl , halogen, alkoxy, alkylthio or alkylsulfonyl; or R ^{d 1} and R ^d or R ^{d 1} and R ^{d 2} together with a carbon atom to form a heterocyclic group of 4, 5, or 6 atoms a ring in which one or two ring atoms are optionally substituted by oxygen or -N-, wherein the heterocyclic ring is optionally substituted by 1 or 2 alkyl groups; R ^{d 3} is hydrogen, alkyl, cycloalkyl or cycloalkyl base.

(i) Preferably, R ^{d 1} is hydrogen, hydroxy, alkoxy, amine, alkylamino or dialkylamino; R ^d and R ^{d 2} are independently hydrogen, alkyl, halogen, alkoxy An alkylthio or alkylsulfonyl group; and R ^{d 3} is hydrogen, alkyl or cycloalkyl.

In the above preferred groups, the following are more preferred groups of the compound, wherein: R ^{d 1} is hydrogen, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino , n-propylamino, isopropylamino, dimethylamino, methyl ethylamino, methyl (n-propyl) amine and methyl (isopropyl) amine; more preferably hydrogen, hydroxyl, methoxy Or a dimethylamino group, more preferably a methoxy group. Alternatively, it is more preferably hydrogen; R ^d and R ^{d 2} are independently fluorine, chlorine, methyl, ethynyl, methoxy, ethoxy, methylthio or methylsulfonyl. R ^{d is more} preferably hydrogen, ethynyl, fluorine, chlorine, methyl, methoxy, methylthio or methylsulfonyl and R ^{d 2} is hydrogen.

R ^{d 1 is} most preferably methoxy or ethoxy, R ^d is hydrogen or methyl, fluorine, chlorine or methoxy and R ^{d 2} is hydrogen.

(1) In the above preferred group of D and the more preferred group thereof, the following are more preferred compounds, wherein: X is -O-; R ¹ is alkoxy, alkylthio or alkyl An alkyl group optionally substituted with a sulfonyl, alkenyl, alkynyl or cycloalkylalkyl group, preferably an alkyl group or a cycloalkylalkyl group, preferably a methyl group, an ethyl group, a n-propyl group or a n-butyl group. , n-pentyl, prop-2-enyl, propyn-2-yl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl Base, methoxymethyl, 2-methoxyethyl, methylthiomethyl, methylsulfonylmethyl or cyclobutylmethyl. More preferably cyclobutylmethyl, ethyl or n-butyl; and R ³ is an alkyl group, an aryl group or cycloalkyl group, preferably 1-methylethyl, 1-methylpropyl, tert-butyl, Cyclopropyl, phenyl or cyclohexyl. R ^{3 is} preferably a tributyl or cyclohexyl group.

(a) In the groups D and D(1) and the more preferred groups thereof, the following are preferred groups of the compounds wherein: E is -COCONHR ⁶ and R ⁶ is hydrogen, alkyl, cycloalkyl, aromatic An alkyl or heteroarylalkyl group, wherein the aromatic ring is optionally substituted by 1 or 2 halogens, R ^{6 is} preferably cyclopropyl, -CH(CH ₃ )R, R is phenyl, 4-chlorophenyl 2,4-Dichlorophenyl, 2,4-difluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl or pyridin-4-yl. R ^{6 is} preferably a cyclopropyl group.

(b) In the groups D and D(1) and the more preferred groups thereof, the following are more preferred groups of the compounds, wherein: E is -COCOOR ^{1 0} , and R ^{1 0} is a definition in the Summary of the Invention. R ^{1 0 is} preferably -CH ₂ C≡CH, -CH ₂ CH=CH ₂ , n-propyl, 2,2-dimethylpropyl, carboxymethyl, methoxycarbonylmethyl, tert-butoxycarbonyl Methyl, -CH ₂ C(O)OCH ₂ C ≡ CH, -CH ₂ C(O)OCH ₂ CH=CH ₂ , -CH ₂ C(O)O(CH ₂ ) ₂ CH ₃ , -CH ₂ C (O)NH ₂ , -CH ₂ C(O)NHCH ₃ , -CH ₂ C(O)N(CH ₃ ) ₂ , -CH ₂ C(O)NHCH ₂ CH=CH ₂ or 2-phenylethyl.

It is necessary to point out that the preferred embodiments of the above description include all combinations of specific and preferred bases unless otherwise stated.

General synthetic method

The compound of the present invention can be produced by the reaction method described below.

The starting materials and reagents used to make these compounds are commercially available from suppliers such as Aldrich Chemical Company (Milwaukee, Wisconsin), Bachem (Torrance, CA) or Sigma (St. Louis, Missouri). Or manufactured by conventional methods described in the following steps in the references, such as Fieser and Fieser's reactants for organic synthesis , Volumes 1-17 (John Wiley and Sons, 1991), Rodd's of carbon compounds Chemistry , Volumes 1–5 and Supplements (Elsevier Science Press, 1989), Organic Reactions , Volumes 1–40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, Fourth Edition) And Larock's Integrated Organic Transformation (VCH Publishing Company, 1989). These methods are merely illustrative of certain methods of synthesizing the compounds of the present invention, and those skilled in the art can make various modifications to these methods with reference to the disclosure of the present invention.

The starting materials and intermediates of the reaction can be separated and purified as desired using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional methods, including physical constants and spectral data.

Unless otherwise specified, the reactions described herein are carried out at atmospheric pressures ranging from about -78 ° C to about 150 ° C, more preferably from about 0 ° C to about 125 ° C and most preferably at about room temperature (or The ambient temperature is carried out, for example, at about 20 °C.

It may be desirable to protect the reactive functional groups such as hydroxyl, amine, imido, thio or carboxy groups in the reaction after the end product is produced to avoid unintended reactions. Known protecting groups can be used according to standard procedures. For examples and see TW Greene and PGM Wuts, " Protective Groups for Organic Chemistry ", John Wiley and Sons, 1999.

The compound of formula (I) can be produced by the following reaction method 1, wherein Y is -OC(O)NH-, E is -COCONR ⁵ R ⁶ and X, R ¹ , R ² , R ³ and R ^{4 are} the inventions The definition within the summary.

Pyrrolidine a compound of formula 1, wherein PG is a suitable carboxy protecting group, preferably an alkyl group, and X and R ^{2 are} as defined in the Summary of the Invention, and an amino acid protecting group PG ₁ such as a third butoxycarbonyl group Deprotection of benzyloxycarbonyl or the like can form a compound of formula 2. The reaction conditions applied to the amino acid protecting group depend on the nature of the protecting group. For example, if PG ₁ is a third butoxycarbonyl group, in an organic solvent such as two The dioxane, tetrahydrofuran or the like can be removed by treatment with an acid of the formula 1, such as hydrochloric acid. Addition and removal of other suitable nitrogen protecting groups can be found in Greene, TW and Wuts, PGM, Protective Bases for Organic Synthesis , John Wiley and Sons, 1999. The compound of formula 1 can be produced by methods known in the art. Some of these methods are described in US 2003191067, US Pat. No. 6,608,027, US Pat. No. 6,268, 207, US Pat.

The amino acid of formula 3 wherein R ³ is a definition of the present invention is treated with a compound of formula 2 under a peptide coupling reaction condition to form a compound of formula 4, wherein Y is -O-C(O)NH- and R ⁴ is an alkyl group. . This reaction is generally carried out in the presence of a suitable coupling agent such as benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) ), O -benzotriazol-1-yl- N,N,N',N' -tetramethylurea hexafluorophosphate (HBTU), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethylurea hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or 1,3-Dicyclohexylcarbodiimide (DCC), which optionally contains 1-hydroxy-benzotriazole (HOBT) and a base such as N,N -diisopropylethylamine, triethylamine, N- Methylmorpholine and the like. The reaction is generally carried out at 20 to 30 ° C, preferably about 25 ° C. Suitable reaction solvents are inert organic solvents such as halogenated organic solvents (for example, dichloromethane, chloroform, etc.), phenylacetonitrile, N,N -dimethylformamide, ether solvents such as tetrahydrofuran, Alkenes, etc. or mixtures thereof. Amino acids of formula 3 are commercially available or can be made by methods well known in the art.

Hydrolysis of the ester group in compound 4 (PG = alkyl) under aqueous alkaline hydrolysis conditions can form a compound of formula 5. The reaction is usually carried out in an aqueous alcohol such as methanol, ethanol or the like with cesium carbonate, lithium hydroxide, sodium hydroxide or the like.

Treatment of a compound of formula 2 with a-hydroxylaminocarbamide of formula 6 under the above-described peptide coupling reaction conditions can form a compound of formula 7. The compound of formula 6 can be made by some of the conventional methods detailed in the following Reference Methods A and B of the examples. Compound 6 can also be produced from Compound 17, which is synthesized in Method 3 below. Briefly, after appropriate amine protecting (eg, third butoxycarbonyl (Boc) urethane), the ester group of compound 17 is removed under alkaline hydrolysis conditions to form the corresponding alpha-hydroxy acid. . The acid is treated with an amine of formula NHR ⁵ R ⁶ under coupling reaction conditions followed by acid catalyzed hydrolysis of the amine protecting group to form a compound of formula 6.

Alternatively, the above coupling step can be carried out by first converting 5 to an active acid derivative such as an acid halide, amber succinimide or the like, and then reacting it with the α-hydroxyketopoxime of the formula 6. The conditions used in this reaction depend on the nature of the active acid derivative. For example, if it is a chlorinated acid derivative of 5, the reaction is carried out in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, pyridine, etc.). Suitable reaction solvents are polar solvents such as phenylacetonitrile, N,N -dimethylformamide, dichloromethane or any suitable mixture thereof. The compound of formula (I) is formed by oxidizing the hydroxyl group of compound 8 with a suitable oxidizing agent such as Dess Martin Periodinane.

The compound of formula (I) can be produced by the following reaction method 2, wherein Y is -NHC(O)NH-, E is -COCONR ⁵ R ⁶ and X, R ¹ , R ² , R ³ and R ^{4 are} the inventions The definition within the summary.

Removal of the Boc group in compound 4 under acid hydrolysis reaction conditions can form the amine compound of formula 9, which upon formation with the alkyl isocyanate forms a ureido compound of formula 10. The reaction is carried out in a suitable organic solvent such as dichloromethane or the like in the presence of an organic base such as triethylamine, pyridine or the like. Urea-based compounds can also be produced by methods known in the art, such as the reaction of compound 9 with carbamoyl halides. The compound is then converted to the compound of formula (I) by Method 1 above. Also, R ⁴ is a compound of the formula (I) other than an alkyl group by substituting an alkyl group with an aryl group, a heteroaryl group or an aralkyl group, an isocyanate or an amine halide.

Likewise, the compounds are in the art by the conventional conditions for producing a compound of Formula 9 by reacting (I) to acylation or the formula R ⁴ COL, or -CHNH- which Y is SO ₂ NH-.

Alternatively, the compound of formula (I) can be produced from compound 4 by deprotecting the protecting group of the acid to produce the corresponding acid. The acid is reacted with a-hydroxyaminocarbamide 6 followed by removal of the Boc [alkyl OC(O)-] group of the product to give the free amine compound. Compound 12 is produced by reaction of an amine compound with an alkyl isocyanate or an amine halide, and is then converted to a compound of formula (I) by oxidation of a hydroxyl group as described above.

The following reactions may be 3 for producing a compound of formula (I) by which E is -COCOOR ^{1 0} and ^{X, Y, R 1, R} 2, R 3 and R ⁴ and R ^{1 0} is defined within the summary of the present invention.

Treatment of the N- Boc-protected amino acid compound of formula 13 with N,O -dimethylamine under conditions well known in the art can form a Weinreb decylamine compound of formula 14. The compound of formula 13 can be prepared from commercially available amino acids and third butoxycarbonyl anhydride under conditions well known in the art. Other suitable amine protecting groups can likewise be utilized. Treatment of compound 14 with a suitable reducing agent such as lithium aluminum hydride in a suitable organic solvent such as tetrahydrofuran or the like can form the corresponding aldehyde of formula 15. Treatment of compound 15 with acetone cyanohydrin to form compound 16, followed by a hydroxy compound of formula R ^{1 0} OH, wherein R ^{1 0} is within the definition of the invention, reacts with an acid halide to produce alpha of formula 17 - a hydroxy ester compound.

Under such conditions the peptide coupling to produce the compound of formula Treatment of compound 5 17, obtained by oxidation of the hydroxy product is formed which is followed Y -OC (O) NH- and R ⁴ is a group of formula (I ) compound. Which Y is -OC (O) NH- and R ⁴ is an alkyl group of a compound of formula (I) which can be converted into other Y and R ⁴ of formula (I) compound as defined within the above summary of the present invention.

The compound of the formula (I) can be produced by the following Reaction Method 4, wherein E is -CONR ^{1 1} R ^{1 2} and X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^{1 1} and R ^{1 2} are Definitions within the abstract of the invention.

Treatment of compound 13 with an amine of formula NHR ^{1 1} R ^{1 2} under the above coupling reaction conditions forms a compound of formula 18. The Boc group is removed under acidic hydrolysis reaction conditions to form compound 19, which is then converted to the compound of formula (I) as described above.

The compound of formula (I) can be produced by the following reaction method 5, wherein E is -COR ⁹ and X, Y, R ¹ , R ² , R ³ , R ⁴ and R ⁹ are definitions within the abstract of the present invention.

The compound of formula 15 can be formed by treating a compound of formula 15 with R ⁹ Li or R ⁹ MX wherein R ⁹ is an organolithium or a genomic reagent as defined in the Summary of the Invention. The reaction is generally carried out at a low reaction temperature such as -78 ° C and in an organic solvent such as tetrahydrofuran or the like. The compound of formula 22 can be formed upon removal of compound 21 from Boc formation upon reaction with compound 5 under the above coupling reaction conditions. Then generates formula (I) after the oxidation of the hydroxy compound which Y is -OC (O) NH- and R ⁴ is an alkyl group. Compounds of formula (I) wherein Y and R ^{4 are} other groups as defined in the abstract of the invention can be prepared according to the above procedure.

The following reactions may be producing a compound of formula 6 (I) by which E is -CHO and ^{X, Y, R 1, R} 2, R 3, R 4 and R ⁹ are defined in the present invention within the summary.

The amine protecting group in compound 23 is removed under acidic hydrolysis reaction conditions, followed by coupling of the amine compound obtained with the compound of formula 5 to yield the compound of formula 24. Compound 24 is then converted to the compound of formula (I) by the above method A or B, which E is -CHO.

In Method A, hydrolysis of the ester group under alkaline hydrolysis conditions can form a compound of Formula 25 which is converted to Weinreb decylamine of Formula 26. Reduction of the guanamine group of formula 26 with a suitable reducing agent such as lithium aluminum hydride to form a compound of formula (I) wherein E is -CHO and Y is -OC(O)NH-.

Alternatively, reduction of the ester group in compound 24 with a suitable reducing agent such as lithium aluminum hydride produces the corresponding alcohol of formula 27 which, after treatment with an oxidizing agent, forms a compound of formula (I) wherein E is -CHO and Y is -OC(O ) NH-. The compound of the formula (I) whose Y is another group can be produced by the above method.

A compound of formula (I) can be converted to other compounds of formula (I). For example, a monohydroxy group can be produced by dealkylation/phenylation of an alkoxybenzyloxy substituent; a monoacid group can be produced by hydrolysis of an ester group; and a corresponding compound of formula (I) can be substituted by The bromine atom above produces a compound of formula (I) containing a cyano group. The cyano group-containing compound of the formula (I) can be converted into a compound having a corresponding carboxyl group by hydrolysis of a cyano group. The carboxyl group can then be converted to a monoester group.

The compound of formula (I) can be prepared as a pharmaceutically acceptable acid addition salt by reaction of a free base form compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a compound of formula (I) can be prepared as a pharmaceutically acceptable base addition salt by reaction of a free acid form compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for use in the manufacture of pharmaceutically acceptable salts of the compounds of formula (I) are illustrated in the definitions of the present invention. Alternatively, a salt of the compound of formula (I) can be prepared using salts of the starting materials or intermediates.

The free acid or free base type of the compound of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base by treatment with a suitable base (eg, ammonium hydroxide solution, sodium hydroxide, and the like). The compound of formula (I) in a base addition salt form can be converted to the corresponding free acid by treatment with a suitable acid such as hydrochloric acid or the like.

The N-oxides of the compounds of formula (I) can be prepared by methods well known to those skilled in the art. For example, by using an oxidizing agent (for example, trifluoroperacetic acid, per maleic acid, perbenzoic acid, peracetic acid, or chloroperoxybenzene) in a suitable inert organic solvent (for example, a halogenated hydrocarbon such as dichloromethane) at 0 °C. Treatment of the unoxidized compound of formula (I) with formic acid or the like can produce N -oxides. Alternatively, N may be manufactured from N- oxides of formula (I) appropriate starting material compounds - oxide.

Suitable inert organic solvents at 0 to 80 ° C (for example, acetonitrile, ethanol, water-containing two Treatment of N -oxides of the compound of formula (I) by a reducing agent such as sulfur, sulfur dioxide, triphenyl phosphate, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc. Unoxidized compounds of formula (I) can be made.

Protected derivatives of the compounds of formula (I) can be prepared by methods well known to those skilled in the art. A detailed description of techniques for forming and removing protecting groups can be found in TW Greene, Protective Groups of Organic Synthesis , Third Edition, John Wiley and Sons, 1999.

Solvates (e.g., hydrates) of the compounds of the invention are conveniently made or formed in the processes of the invention. The hydrate of the compound of the present invention can be conveniently produced by recrystallization using an organic solvent such as an aqueous/organic solvent mixture of dioxin, tetrahydrofuran or methanol.

Non-image isomers of compounds of formula (I) having different physical properties (e.g., melting point, boiling point, solubility, activity, etc.) can be made and can be readily separated by virtue of their dissimilarity. The non-image isomers may be separated by chromatography, or preferably by separation/redissolution techniques, depending on their solubility. The optically purified isomer is collected by a practical method that does not result in its racemization to the palm center. Techniques for isolating stereoisomers of compounds from racemic mixtures are described in detail in Jean Jacques Andre Collet, Samuel H. Wilen, Mirror Image Isomers, Racemic Mixtures and Separation Methods , John Wiley and Sons (1981).

Pharmacology and practicality

The compounds of the present invention are inhibitors of hepatitis C virus (HCV) replication and are therefore useful for the treatment of hepatitis C infection. The inhibitory activity of the compound of formula (I) can be determined by methods well known to those skilled in the art. A suitable in vitro assay for determining the activity of a compound of the invention against HCV replication is described in Biological Example 1 below.

Dosing method and pharmaceutical composition

In general, a therapeutically effective amount of a compound of formula (I) can be administered by any of the usual and accepted routes known in the art, alone or in combination with one or more other therapeutic agents. The therapeutically effective dose varies greatly depending on the severity of the disease, the age and relative health of the animal, the efficacy of the compound used, and other factors. For example, a therapeutically effective dose of a compound of formula (I) can range from about 10 micrograms per kilogram of body weight per day (micrograms per kilogram) to about 100 milligrams per kilogram of body weight per day (mg/kg), typically from about 100 micrograms per kilogram per day to about 10 mg / kg / day. Thus, a therapeutically effective dose for a patient of 80 kg is from about 1 mg/day to about 8 g/day, typically from about 1 mg/day to about 800 mg/day. In general, a person skilled in the art can determine the therapeutically effective dose of a compound of formula (I) for the treatment of a known condition by personal knowledge and disclosure of the present application.

The pharmaceutical composition of the compound of formula (I) can be administered by one of the following routes: oral, systemic (e.g., transdermal, intranasal or suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). The composition may be in the form of a lozenge, a pill, a capsule, a semisolid, a powder, a sustained release formulation, a solution, a suspension, an elixir, a spray, or a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient. Any other suitable composition. Acceptable excipients are non-toxic, aid in administration, and do not produce undesirable effects on the treatment of the active ingredients. Such excipients can be any solid, liquid, semi-solid or, in the case of a spray composition, typically a gaseous excipient as is known to those skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, sputum gel, magnesium stearate, stearin Sodium, glyceryl monostearate, sodium chloride, dried skim milk powder, and the like. The liquid and semi-solid excipients can be selected from the group consisting of water, ethanol, glycerin, propylene glycol, and various oils including petroleum, animal, vegetable or synthetic (eg, peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred carriers for use in particular injectable solutions include water, physiological saline, aqueous dextrose and glycerol.

The amount of the compound of formula (I) within the composition varies greatly depending on the type of formulation, the volume of the unit dose, the type of excipient, and other factors known to those skilled in the medical arts. In general, the composition of the compound of formula (I) for the treatment of a known condition contains from 0.01% by weight to 90% by weight of active ingredient, preferably from 5% by weight to 50% by weight, the remainder being excipients or Various excipients. When the pharmaceutical composition is used for continuous treatment, it is preferably administered in a unit dosage form, or when it is particularly necessary to alleviate the symptoms, it is administered in a unit dosage form without limitation. The following are representative pharmaceutical formulations containing a compound of formula (I).

In some embodiments, a compound of formula (I) can be administered to a patient in need of treatment with a second antiviral agent. Examples of suitable antiviral agents include interferons such as Intron A, Roferon A and pegylated interferons such as PEG-intron, Pegasys Ribavirin; Viramidine; Levovirin; HCV polymerase inhibitors such as Valopicitabine, R 1626 (Roche), HCV-796 (Viropharma/Wyeth); and Toll type Receptor agonists such as ANA-975 (Anadys Pharmaceuticals). The compound of formula (I) may be combined with the above therapeutic agents or administered separately. In addition, the compound of formula (I) can be administered before or after administration of the second antiviral agent according to the physician's prescription.

Example

The invention is further illustrated by the following examples of the production method of the compound of the formula (I) according to the invention.

Reference Method A

Synthesis of [1 S -(cyclopropylaminecarbonylhydroxymethyl)butyl]aminocarboxylic acid tert-butyl ester

step 1

NMM (34.9 g, 0.35 mol) was slowly added to Boc-Nva-OH (25 g, 0.115 mol), N,O -dimethylhydroxylamine salt in dichloromethane (300 mL) over 30 min. A mixture of acid salt (12.34 g, 0.127 mol), EDC (33.07 g, 0.173 mol), HOBt (22.9 g, 0.15 mol). The reaction was placed at room temperature for 2 hours and then diluted with 2000 ml EtOAc, washed with NaHCO _3, H ₂ O and brine, and dried over MgSO _4. The solvent was removed on a rotovap to give <RTI ID=0.0>>

Step 2

LAH (1 gram in THF, 27.7 ml) was slowly added to [1S-(methoxymethylaminecarbonyl)butyl]carbamic acid tert-butylate in anhydrous THF (100 mL) at -78 °C. Ester (7.2 g, 27.7 mmol) solution. After two hours, the reaction mixture was cooled by slowly adding 1 equivalent of HCl (20 mL) and then allowed to warm to room temperature. The reaction mixture was diluted with EtOAc (600 mL), 1 equivalent of HCl, H ₂ O and brine, and dried over MgSO _4. The solvent was removed to give (1S-methylmercaptobutyl) carbamic acid tert-butyl ester (4.8 g) as an oil.

Step 3

Acetic acid (2.28 g, 38 mmol) was added to cyclopropyl isocyanide (1.91 g, 28.5 mmol), (1S-methylmercaptobutyl)amine in dichloromethane (100 mL) at 0 °C. A solution of tert-butyl formate (3.8 g, 19 mmol). After the addition was completed, the reaction mixture was warmed to 25 ° C and stirred for 6 hours. The reaction mixture was diluted with EtOAc (200 mL), then washed in a saturated solution of NaHCO ₃ and brine (30 mL) and dried over MgSO _4. After the solvent was removed, the title compound (3.5 g, m.

Reference Method B

Synthesis of ( 1S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-hydroxyethyl)carbamic acid tert-butyl ester

step 1

NMM (9.11 g, 90 mmol) was slowly added to Boc-L-cyclobutylphenylalanine DIPA (10.33 g, 30 mmol), N, in dichloromethane (200 mL) over 30 min . A mixture of O -dimethylhydroxylamine hydrochloride (3.22 g, 33 mmol), EDC (8.63 g, 45 mmol), HOBt (5.52 g, 36 mmol). After 2 hours, the reaction mixture was diluted with EtOAc (1000 mL), NaHCO _3, H ₂ O and brine, and dried over MgSO _4. The solvent was removed to give [2-cyclobutyl-1S-(methoxymethylaminecarbonyl)ethyl]carbamic acid tert-butyl ester (7.1 g).

Step 2

LAH (1 gram in THF, 15 mmol) was slowly added to [2-cyclobutyl-1 S- (methoxymethylamine carbonyl) in anhydrous THF (100 mL) at -78 °C. A solution of ethyl butyl carbamic acid tert-butyl ester (4.3 g, 15 mmol). After two hours, the reaction mixture was cooled by slowly adding 1 equivalent of HCl (15 mL) and then the mixture was warmed to room temperature after the addition was completed. The reaction mixture was diluted with EtOAc (500 mL), 1 equivalent of HCl, H ₂ O and brine, and dried over MgSO _4. The solvent was removed to give tert-butyl (2-cyclobutyl-1 S -methylmercaptoethyl)carbamate (2.95 g) as an oil.

Step 3

Cyclopropyl at 0 ℃ Acetic acid (1.56 g, 26 mmol) was added dichloromethane (20 mL) isocyanide (1.21 g, 18 mmol), (2-cyclobutyl -1 S - A solution of tert-butyl carbenylethyl)carbamate (2.95 g, 13 mmol). After the addition was completed, the reaction mixture was warmed to 25 ° C and stirred for additional 4 hours. The reaction mixture was diluted with 200 ml EtOAc, then saturated NaHCO ₃ solution and brine and dried over MgSO _4. After the solvent was removed, the title compound (3.8 g, m.

Step 4

Aqueous NaOH (1 eq, 15 mL) was added to 2S -t-butoxycarbonylamino-3-cyclobutyl-1-cyclopropylaminocarbonyl propyl acetate in ethanol (50 mL) at room temperature. 3.8 grams, 10.7 millimoles) solution. After 2 hours, the methanol was removed and the concentrate was extracted with ethyl acetate. Ethyl acetate in brine and dried over MgSO _4. The solvent was removed and the residue was crystalljjjjjjjjjjjjjj

Example 1

Synthesis of 1-[2 S -(3-tert-butylureido)-3,3-dimethylbutylidene]-4 R -(7-methoxy-2-pyrazole-1-yl-quinoline-4 -yloxy)pyrrolidine-2 S -formic acid (1 S -cyclopropylamine oxalylbutyl) decylamine (7)

step 1

Commercially available N -Third-Boc-cis-4 S -hydroxy-L-proline acid in triphenylphosphine (594 mg, 2.27 mmol) in dry THF (15 mL) at 0 °C Ester (370 mg, 1.51 mmol) and 7-methoxy-2-pyrazol-1-ylquinolin-4-ol (PCT Application Publication No. WO 2000059929) (400 mg, 1.66 mmol), followed by DIAD (0.36 mL, 1.81 mmol) was slowly added under nitrogen. The reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The crude reaction mixture was then concentrated and purified by flash chromatography to afford < RTI ID=0.0>> 1,2-Dicarboxylic acid 1-tert-butyl ester-2 S -methyl ester (1).

Step 2

Will be two 4.0 R HCl in alkane (3.0 mL) was added to 4 R -(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine in dichloromethane (1 mL) A solution of 1-1,3-butyric acid 1-tributyl ester-2 S -methyl ester (200 mg, 0.43 mmol). After 1 hour, the reaction mixture was concentrated and dried to obtain a white solid of 4 R - (7- methoxy-2-pyrazol-1-yl - quinolin-4-yloxy) pyrrolidine -2 S - Methyl formate hydrochloride (2).

Step 3

Boc-L-third leucine-OH (38.1 mg, 0.165 mmol), HATU (69 mg, 0.182 mmol) and DIPEA (0.1 mL, 0.5 mmol) were added to dichloromethane/DMF ( 4 R -(7-Methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine-2 S -carboxylic acid methyl ester hydrochloride in 2.0 ml, 1:1) A solution of 67 mg, 0.165 mmol) was then stirred at room temperature. After 16 hours, diluted with ethyl acetate and 1 equivalent of HCl, saturated NaHCO ₃ and brine the reaction mixture. Dried (MgSO ₄₎ the ethyl acetate layer was filtered and evaporated to dryness to obtain mass production of 1- (2 S - third-butoxycarbonylamino-3,3-dimethyl-butyl acyl) -4 R - (7- Methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine- 2S -formic acid methyl ester (3).

Step 4

Will be two 4.0 equivalents in dioxane (3.0 ml) was added HCI unpurified 1- (2 S - third-butoxycarbonylamino-3,3-dimethyl-butyl acyl) in dichloromethane (1 mL) -4 R - (7 Methyl 2-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine- 2S -carboxylate solution. After 1 hour, the reaction mixture was concentrated and dried to obtain a white solid was used in the next step without further purification of the 1- (2 S - acyl amino-3,3-dimethoxy-butyl) -4 R - (7- Methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidin-2 S -carboxylic acid methyl ester hydrochloride.

Step 5

Add triethylamine (0.06 ml, 0.413 mmol) and tributyl butyl cyanate (0.02 mL, 0.165 mmol) to 1-( 2S -amino-3 in dichloromethane (3.0 mL) ,3-dimethylbutylidene)-4 R- (7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine-2 S -formic acid methyl ester hydrochloride (0.165 The solution was stirred and the mixture was stirred at room temperature. After 16 hours, diluted with dichloromethane and 1 equivalent of HCl, saturated NaHCO ₃ and brine and the reaction mixture was washed. The dichloromethane layer was then evaporated to dryness to obtain 1- [2 S - (3- tert-butyl ureido) -3,3-dimethyl-butyl acyl] -4 R - (7- methoxy-2-yl Methyl oxazol-1-yl-quinolin-4-yloxy)pyrrolidine-2 S -carboxylate (4).

Step 6

Methanol (6.0 ml), THF (3.0 mL) and 1N NaOH (6 mL) 1- [2 S - (3- tert-butyl ureido) -3,3-dimethyl-butyl acyl] -4 R - Methyl (7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine- 2S -carboxylate. After 1 hour at room temperature, the reaction mixture was concentrated with 1N HCl, acidified and ethyl acetate. Then through the brine and the combined ethyl acetate layer was dried (MgSO _4). Then filtered and the ethyl acetate layer was evaporated to dryness to obtain 1- [2 S - (3- tert-butyl ureido) -3,3-dimethyl-butyl acyl] -4 R - (7- methoxy-2 -pyrazol-1-yl-quinolin-4-yloxy)pyrrolidin-2 S -carboxylic acid (5).

Step 7

[ 1S- (Cyclopropylaminocarbonylhydroxymethyl)butyl]aminocarbamic acid tert-butyl ester (48 mg, 0.165 mmol) was dissolved in dichloromethane (3.0 mL) then TFA (3.0) ML). After stirring at rt for 1 h, the reaction mixture was evaporated to dryness to obtain a white solid of 3 S - amino-2-hydroxycaproic acid cyclopropylmethyl Amides TFA salt. The 3 S - 1- [2 S hydroxycaproic acid cyclopropylmethyl-amino-2-amine TFA salt was added dichloromethane acyl /DMF(1:1;6.0 mL) was - (3-t-butyl-ureido) -3,3-dimethylbutylidene]-4 R- (7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine-2S-carboxylic acid solution, followed by HATU ( 75 mg, 0.198 mmol) and EIPEA (0.1 ml, 0.7 mmol). After 24 hours at room temperature, diluted with ethyl acetate and 1 equivalent of HCl, the reaction mixture was NaHCO ₃ and brine. Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness. The crude product was then taken up in dry dichloromethane (10.0 mL) and EtOAc <RTI ID=0.0> After stirring at room temperature for 2 hours, and 0.26 mole Na ₂ S saturated NaHCO _{3 2} O ₃ and cooling the reaction mixture was extracted with ethyl acetate. NaHCO ₃ and then with saturated brine and the ethyl acetate layer was combined. The title compound (7) having an HPLC purity of >99% was obtained by purification by preparative HPLC.

¹ H NMR: (DMSO-d ₆ ) δ 8.76~8.70 (m, 2H); 8.22 (d, J = 6.8 Hz, 1H); 8.11 (d, J = 9.6 Hz, 1H); 7.87 (d, J = 1.2 Hz, 1H); 7.45 (s, 1H); 7.27 (d, J = 2.4 Hz, 1H); 7.00 to 6.97 (dd, J = 2.8 and 9.6 Hz, 1H); 6.64~6.62 (m, 1H); 5.92(brs,1H);5.49(brs,1H);5.00~4.96(m,1H);4.55~4.49(m,2H);4.18(d,J=5.6Hz,1H);3.90(s,3H) ; 3.91~3.82(m,1H); 3.54(brs,1H); 2.75~2.72(m,1H);2.54~2.51(m,1H); 2.17~2.14(m,1H);1.69~1.66(m, 1H); 1.40~1.34 (m, 3H); 1.13 (m, 9H); 0.93 (m, 9H); 0.90 to 0.82 (m, 3H); 0.65 to 0.53 (m, 4H). MS (M ⁺ +1) 733.

Example 2

Synthesis of 1-[2 S -(3-tert-butylureido)-3,3-dimethylbutylidene]-4 R -(7-methoxy-2-pyrazole-1-yl-quinoline-4 -yloxy)pyrrolidine-2-carboxylic acid (1 S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-oxoethyl)decylamine (9)

step 1

(1 S -Cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-hydroxyethyl)carbamic acid tert-butyl ester (51 mg, 0.165 mmol) was dissolved in dichloromethane (3.0 mL) then TFA (3.0 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was evaporated to dryness to give a white solid of 3 S - amino-4-cyclobutyl - N - cyclopropyl-2-hydroxybutyric Amides TFA salt. Add 3- S -Amino-4-cyclobutyl- N -cyclopropyl-2-hydroxybutanamine TFA salt to 1-[2 S -(() in dichloromethane/DMF (1:1; 6.0 mL) 3-tert-butylureido)-3,3-dimethylbutylidene]-4 R- (7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine- 2 S -formic acid solution followed by HATU (75 mg, 0.198 mmol) and EIPEA (0.1 mL, 0.7 mmol). After 24 hours at room temperature, diluted with ethyl acetate and 1 equivalent of HCl, the reaction mixture was saturated NaHCO ₃ and brine. Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness. The crude product was then taken up in dry dichloromethane (10.0 mL) and EtOAc <RTI ID=0.0> After stirring at room temperature for 2 hours, and 0.26 mole Na ₂ S saturated NaHCO _{3 2} O ₃ and cooling the reaction mixture was extracted with ethyl acetate. NaHCO ₃ and then with saturated brine and the ethyl acetate layer was combined. The title compound (9) with an HPLC purity of >99% was obtained by purification by preparative HPLC.

¹ H NMR: (DMSO-d ₆ ) δ 8.76~8.69 (m, 2H); 8.19 (d, J = 8.0 Hz, 1H); 8.10 (d, J = 8.0 Hz, 1H); 7.87 to 7.86 (m, 1H); 7.45 (s, 1H); 7.27 (d, J = 2.8 Hz, 1H); 7.00 to 6.97 (dd, J = 2.8 and 9.6 Hz, 1H); 6.64~6.62 (m, 1H); 5.93 (brs ,1H);5.48(brs,1H);5.00~4.96(m,1H);4.53~4.49(m,2H);4.18(d,J=9.2Hz,1H);3.90(S,3H);3.91~ 3.82(m,1H); 3.42(brS,2H); 2.75~2.72(m,1H); 2.54~2.51(m,1H); 2.17~2.14(m,1H);1.96~1.89(m,2H); 1.78~1.50 (m, 6H); 1.13 (m, 9H); 0.94 (m, 9H); 0.65 to 0.53 (m, 4H). MS (M ⁺ +1) 759.

Example 3

Synthesis of 1-[2 S -(3-tert-butylureido)-3,3-dimethylbutylidene]-4 R -(5-chloropyridin-2-yloxy)pyrrolidine-2 S -formic acid ( 1 S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-oxoethylethylamine (15)

Over 15 minutes at 23 ℃ the potassium t-butoxide (3 mmol) was added in small portions in DMSO commercially third -Boc- (2 S, 4 R) - hydroxy proline (1 mmol Mo ear). The mixture was stirred at 23 ° C for 30 minutes and then cooled to 0 ° C before being added to a small portion of 2,5-dichloropyridine (1.1 mmol) in 10 minutes. The reaction mixture was stirred at 23 ° C for 16 hours. The obtained suspension was poured into 5% aqueous citric acid and then extracted with EtOAc. EtOAc layer was washed brine and then dried Combining (MgSO _4). The organic portion was filtered and concentrated to give a white solid. Dissolving the solid material in two 4.0 equivalents of HCl in alkane (10 mL). After 1 hour, the reaction mixture was concentrated and dried to obtain 4 R - (5- chloro-pyridin-2-yloxy) pyrrolidine -2 S - methyl ester hydrochloride.

step 1

Boc-L-third leucine-OH (192 mg, 0.0.829 mmol), HATU (347 mg, 0.912 mmol) and DIPEA (0.37 mL, 2.07 mmol) were added to dichloromethane/ a solution of 4 R -(5-chloropyridin-2-yloxy)pyrrolidine-2 S -formic acid methyl ester hydrochloride (242 mg, 0.829 mmol) in DMF (10 mL, 1:1) The reaction mixture was stirred at room temperature. After 16 hours, diluted with ethyl acetate and the reaction mixture was washed with saturated NaHCO ₃ and brine. Dried (MgSO ₄₎ the ethyl acetate layer was filtered and evaporated to dryness to obtain mass production of 1- (2 S - third-butoxycarbonylamino-3,3-dimethyl-butyl acyl) -4 R - (5- Chloropyridin-2-yloxy)pyrrolidine-2 S -formic acid methyl ester (11).

Step 2

Methanol (5.0 ml), THF (3.0 mL) and 1N NaOH (5 ml) 1- (2 S - third-butoxycarbonylamino-3,3-dimethyl-butyl acyl) -4 R - (5- Methyl chloropyridin-2-yloxy)pyrrolidine-2 S -carboxylate. After 2 hours at room temperature, the reaction mixture was concentrated with 1N EtOAc, acidified and ethyl acetate. Then through the brine and the combined ethyl acetate layer was dried (MgSO _4). Then filtered and the ethyl acetate layer was evaporated to dryness to obtain 1- (2 S - third-butoxycarbonylamino-3,3-dimethyl-butyl acyl) -4 R - (5- chloro-pyridin-2-yloxy Pyrrolidine-2 S -formic acid (12).

Step 3

Will be two 4.0 equivalent of HCl in alkane (11.0 ml) was added ( 1S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-hydroxyethyl)carbamic acid tert-butyl ester (214 mg, 0.83 mmol). After 1 hour, the reaction mixture was concentrated and dried to obtain a white solid of 3 S - amino-4-cyclobutyl - N - acyl cyclopropyl-2-hydroxybutyrate hydrochloride. The 1- (2 S /DMF(1:1;10.0 mL dichloromethane) in the - third-butoxycarbonylamino-3,3-dimethyl-butyl acyl) -4 R - (5- chloro-2- Benzyl)pyrrolidine-2 S -formic acid, EDC (238 mg, 1.24 mmol), HOBt (190 mg, 1.24 mmol) and NMM (0.6 mL, 3.32 mmol) were added to the 3 S -amino group. 4-cyclobutyl- N -cyclopropyl-2-hydroxybutanamine. After 16 hours, diluted with ethyl acetate and saturated NaHCO ₃ and brine and dried (MgSO ₄₎ the reaction mixture. Then, the ethyl acetate layer was filtered, concentrated and purified by flash chromatography to obtain a yield of 58% yield of {1-[4 R -(5-chloropyridin-2-yloxy)-2 S -(1 S - Cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-hydroxyethylaminecarbonyl)pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}aminocarboxylic acid tert-butyl ester (13).

Step 4

Will be two {1- [4 R 4.0 equivalents of HCl in dioxane (3.0 ml) was added dichloromethane (2 mL) was - (5-chloro-2-yloxy) -2 S - (1 S - cyclobutylmethyl -2-cyclopropylaminecarbonyl-2-hydroxyethylaminecarbonyl)pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}carbamic acid tert-butyl ester (313 mg, 0.482 mmol) ). After 1 hour, the reaction mixture was concentrated and dried to obtain a white solid of 1- (2 S - acyl amino-3,3-dimethoxy-butyl) -4 R - (5- chloro-pyridin-2-yloxy) pyrrolidin Pyridin-2 S -formic acid (1 S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-hydroxyethyl)guanamine hydrochloride.

Step 5

1- Triethylamine (0.02 mL, 0.154 mmol) was added dichloromethane (3.0 mL) of (2 S - acyl amino-3,3-dimethoxy-butyl) -4 R - (5- chloropyridine - 2-yloxy)pyrrolidinium- 2S -carboxylic acid ( 1S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-hydroxyethyl)guanamine hydrochloride (45 mg, 0.077 mmol) solution . After 5 minutes at room temperature, tributyl isocyanate (0.01 mL, 0.077 mmol) was added and the reaction mixture was stirred at room temperature. After 16 hours, diluted with dichloromethane and 1 equivalent of HCl, saturated NaHCO ₃ and brine and the reaction mixture was washed. The dichloromethane layer was then evaporated to dryness to obtain 1- [2 S - (3- tert-butyl ureido) -3,3-dimethyl-butyl acyl] -4 R - (5- chloro-pyridin-2-yloxy Pyrrolidine-2 S -formic acid (1 S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-hydroxyethyl)decylamine (14).

Step 6

1-[2 S -(3-Terhanylureido)-3,3-dimethylbutylidene]-4 R- (5-chloropyridin-2-yloxy)pyrrolidin-2 S -carboxylic acid ( 1 S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-hydroxyethyl)guanamine dissolved in anhydrous dichloromethane (4.0 mL) then dist Martin iodoranane (44 mg, 0.103 mmol) ). After stirring at room temperature for 2 hours, and 0.26 mole Na ₂ S saturated NaHCO _{3 2} O ₃ and cooling the reaction mixture was extracted with ethyl acetate. NaHCO ₃ and then with saturated brine and the ethyl acetate layer was combined. The title compound (15) with an HPLC purity >90% was obtained by purification by preparative HPLC.

¹ H NMR: (DMSO) 8.91 to 8.73 (m, 1H); 8.30 to 8.24 (m, 2H); 7.92 to 7.80 (m, 1H); 6.94 to 6.84 (m, 1H); 5.97 (brs, 1H); 5.50(s,1H);5.00~4.95(m,1H);4.54~4.52(m,1H);4.17~3.88(m,3H);2.75~2.72(m,1H);2.54~2.51(m,1H) ); 2.40~2.32 (m, 1H); 2.17~1.60 (m, 10H); 1.13 (m, 9H); 0.91 (m, 9H); 0.67~0.58 (m, 4H). MS (M ⁺ +1) 648.

Example 4

Synthesis of {1 S -[2 S -(1 S -cyclopropylamine oxalylbutylcarbonyl)-4 R -(7-methoxy-2-pyrazol-1-ylquinolin-4-yl Oxypyrrolidine-1-carbonyl]-2,2-dimethylpropyl}aminocarboxylic acid tert-butyl ester (16)

This was carried out according to the method described in Example 1 above to give {1 S -[2 S -(1 S -cyclopropylamine-decyl butylamine carbonyl)-4 R -(7-methoxy-2- Pyrazol-1-ylquinolin-4-yloxy)pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}aminocarboxylic acid tert-butyl ester. MS: 734 (M+1) MS: 734 (M+1)

Example 5

Synthesis of {1 S -[2 S -(1 S -cyclopropylamine oxalylbutyl carbonyl)-4 R -(7-methoxy-2-phenylquinolin-4-yloxy)pyrrole Third butyl pyridine-1-carbonyl]-2,2-dimethylpropyl}carbamate (17)

This was carried out according to the method described in Example 4 above, but substituting 7-methoxy-2-phenyl-quinolin-4-ol for 7-methoxy-2-pyrazol-1-yl-quinoline- 4-Alkyl to give the title compound. MS: 744 (M+1)

Example 6

Synthesis of {1 S -[4 R -(5-chloropyridin-2-yloxy)-2 S -(1 S -cyclopropylamine oxalylbutylaminecarbonyl)pyrrolidine-1-carbonyl]-2 ,2-dimethylpropyl}amino carboxylic acid tert-butyl ester (18)

This was carried out according to the method described in Example 4 above, but substituting 4 R -(7-methoxyl) with 4 R -(5-chloropyridin-2-yloxy)pyrrolidinium-2-carboxylate hydrochloride 2-Pyrazol-1-ylquinolin-4-yloxy)pyrrolidinium- 2S -carboxylic acid methyl ester hydrochloride afforded the title compound. MS: 622 (M + 1)

Example 7

Synthesis of {1 S -[4 R -(5-chloropyridin-2-yloxy)-2 S -(1 S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-oxo-ethylaminecarbonyl) Pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}aminocarboxylic acid tert-butyl ester (19)

This was carried out according to the method described in Example 4 above, but substituting 4 R -(7-methoxyl) with 4 R -(5-chloropyridin-2-yloxy)pyrrolidinium-2-carboxylate hydrochloride 2-pyrazol-1-ylquinolin-4-yloxy)pyrrolidine-2 S -carboxylic acid methyl ester hydrochloride and (1 S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2- The tert-butyl [ 1,3- (cyclopropylaminocarbonylhydroxymethyl)butyl]carbamate is substituted with the butyl hydroxyethyl) carbamic acid to give the title compound. MS: 648 (M+1)

Example 8

Synthesis of 1-[2 S -(3-tert-butylureido)-3,3-dimethylbutylidene]-4 R -(5-chloropyridin-2-yloxy)pyrrolidine-2 S -formic acid ( 1 S -cyclopropylamine oxalylbutyl) decylamine (20)

This was carried out according to the method described in Example 3 above, but substituted with [1 S -(cyclopropylaminecarbonylhydroxymethyl)butyl]aminocarbamic acid tert-butyl ester (1 S -cyclobutylmethyl-2-ring The butylaminocarbonyl-2-hydroxyethyl)butyl]carbamic acid tert-butyl ester afforded the title compound. MS: 621 (M + 1)

Example 9

Synthesis of 1-[ 2S- (3-tert-butylureido)-3,3-dimethylbutylidene]-4 R- (6-methoxyisoquinolin-1-yloxy)pyrrolidine-2 S -formic acid (1 S -cyclopropylamine oxalylbutyl) decylamine (21)

step 1

Ethyl chloroformate (4.3 ml, 44.5 mmol) was added dropwise to 3-methoxycinnamic acid (5.3 g, 29.7 mmol) and triethylamine (8.3 ml) in acetone (35 mL) at 0 °C. , 59.4 millimoles) solution. After 1 hour at 0 ° C, aqueous sodium azide (3.1 g, 47.5 mmol, 16 mL water) was added dropwise and then the mixture was stirred at 23 ° C for 16 hours. Water (50 mL) was added to the mixture and the volatiles were removed in vacuo. The organic layer with toluene (3x25 mL) and then dried to produce the sludge (MgSO ₄₎ binding. The dried solution was filtered and then added dropwise to a solution of diphenylmethane (25 mL) and tributylamine (14.2 mL, 59.4 mmol) at 190 °C. The added toluene was distilled off. After all the additions were completed, the reaction temperature was raised to 210 ° C for 2 hours. After cooling, the precipitated product was collected by filtration and washed with hexanes and dried under vacuo to give 6-methoxy-2H-isoquinolin-1-one (1.7 g, 9.7 mM, 33% yield). MS m / z 176 (M ⁺ +H)

Step 2

A suspension of 6-methoxy-2H-isoquinolin-1-one (900 ml, 5.1 mmol) in POCl ₃ (4 mL) was heated to 110 ° C for 3 hours (a transparent solution was produced upon heating) ). After 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was poured into ice water (10 mL), and then adjusting the pH to 10 followed by NaOH and extracted with CHCl ₃ (3x25 mL) to 3 equivalents. In conjunction brine CHCl ₃ layer was dried (MgSO _4). The organic layer was then filtered, concentrated and purified by flash chromatography to afford 1-chloro-6-methoxyisoquinoline as a white solid (720 mg, 3.7 mM, 73% yield). ¹ H NMR (CD ₃ OD): 8.23 (d, 1H, J = 8.8 Hz); 8.11 (d, 1H, J = 6.0 Hz); 7.69 (d, 1H, J = 6.0 Hz); 7.37 to 7.33 (m) , 2H); 3.97 (s, 3H). MS m / z 194 (M ⁺ +H)

Step 3

At 23 ℃ within 15 minutes to potassium t-butoxide (997 mg, 8.88 mmol) was added in small portions DMSO commercially available N (20 mL) - the third -Boc- (2 S, 4 R) - Hydroxyproline (684 mg, 2.96 mmol). The mixture was stirred at 23 ° C for 30 minutes and then cooled to 0 ° C. 1-Chloro-6-methoxyisoquinoline (600 mg, 3.11 mmol) was added in small portions over 10 min at 0 °C. The reaction mixture was stirred at 23 ° C for 16 hours. The obtained suspension was poured into 5% aqueous citric acid (100 mL). In conjunction with EtOAc layer was washed brine and then dried (MgSO _4). Filtration and concentration of the organic layer gave ( 2S , 4R )-(6-methoxyisoquinolin-1-yloxy)pyrrolidin-1,2-dicarboxylic acid-1-t-butyl Ester (1.04 g, 2.68 mmol, 91% yield). MS m / z 194 (M ⁺ +H). It was used in the next step for the crude material which was not further purified.

Step 4

Will be two 4.0 equivalent of HCl in alkane (10 ml) was added to [ 1S- (cyclopropylaminecarbonylhydroxymethyl)butyl]carbamic acid tert-butyl ester (100 mg, 0.35 mmol). After 1 hour, the reaction mixture was concentrated and dried to give the corresponding white salt. (2 S ,4 R )-(6-Methoxyisoquinolin-1-yloxy)pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester (136 mg, 0.35 mmol) HATU (160 mg, 0.42 mmol) and DIPEA (0.2 mL, 1.05 mmol) were added to the above hydrochloride salt in DCM/DMF (8:3, 11.0 mL). After 2 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness to obtain 2 S - [1 S - (carbonyl cyclopropylamine hydroxymethyl) butylamine carbonyl] -4 R - (6- methoxy Isoquinolin-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester.

Step 5

Will be two 4.0 equivalents of HCl in alkane (10 ml) was added to the above unpurified compound. After 1 hour, the reaction mixture was concentrated and dried to give the corresponding crude salt as a white solid. 2S-(3-tert-butylureido)-3,3-dimethylbutyric acid (81 mg, 0.35 mmol), HATU (160 mg, 0.42 mmol) and DIPEA (0.2 mL, 1.05 m) The above amine hydrochloride salt was added to DCM/DMF (8:3, 11.0 mL). After 16 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness.

Step 6

The unpurified product was then dissolved in anhydrous dichloromethane (10.0 mL) and EtOAc EtOAc (EtOAc &lt The reaction mixture was then stirred at room temperature for 2 hours, and 0.26 mole Na ₂ S was cooled saturated NaHCO _{3 2} O ₃ and extracted with ethyl acetate (3x). And washed with saturated NaHCO ₃ (2x) and brine (1x) washing the ethyl acetate layer was combined. Production level was purified by HPLC to obtain a HPLC purity of> 95% of 1- [2 S - (3- tert-butyl ureido) -3,3-dimethyl-butyl acyl] -4 R - (6- methoxy Isoquinolin-1-yloxy)pyrrolidine- 2S -formic acid (1 S -cyclopropylamine oxalylbutyl) decylamine (21). ¹ H NMR: (DMSO-d ₆ ) 8.74 (d, 1H, J = 4.8 Hz); 8.28 (d, 1H, J = 4.8 Hz); 8.15 (d, 1H, J = 9.2 Hz); 7.97 (d, 1H, J=6.0Hz); 7.34~7.32(m, 2H); 7.11~7.08(m,1H); 5.94(brs,1H); 5.72~5.70(m,1H); 5.04~5.00(m,1H) ;4.58(t,1H,J=8.4Hz);4.34~4.22(m,2H);3.91(s,3H);3.90~3.86(m,1H);2.79~2.74(m,1H);2.54~2.51 (m,1H); 2.18~2.11(m,1H);1.77~1.70(m,1H);1.48~1.38(m,3H);1.15(m,9H);0.91(m,9H);0.90~0.86 (m, 3H); 0.69 to 0.56 (m, 4H). MS m / z 667 (M ⁺ +H), 689 (M ⁺ +Na), 665 (M ⁺ -H)

Example 10

Synthesis of 1-[ 2S- (3-tert-butylureido)-3,3-dimethylbutylidene]-4 R- (6-methoxyisoquinolin-1-yloxy)pyrrolidine-2 S -formic acid (2-cyclopropylaminocarbonyl-1 S -cyclopropylmethyl- 2S -sideoxyethyl)decylamine (23)

step 1

(2 S ,4 R )-(6-Methoxyisoquinolin-1-yloxy)pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester (78 mg, 0.2 mmol) , HATU (91 mg, 0.4 mmol) and DIPEA (0.1 mL, 0.6 mmol) were added to ( S )-3-amino-4, N -di in DCM/DMF (5: 1.5, 6.5 mL) Cyclopropyl-2-hydroxybutyrate hydrochloride (47 mg, 0.2 mmol). After 16 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness to obtain 2 S - (2- cyclopropyl-aminocarbonyl -1 S - cyclopropylmethyl -2 (±) - aminocarbonyl-hydroxyethyl) -4 R- (6-Methoxyisoquinolin-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (22).

Step 2

Will be two 4.0 equivalents of HCl in alkane (5.0 ml) was added to the above unpurified compound. After 1 hour, the reaction mixture was concentrated and dried to give the corresponding crude salt as a white solid. 2 S -(3-tert-butylureido)-3,3-dimethylbutyric acid (46 mg, 0.2 mmol), HATU (91 mg, 0.24 mmol) and DIPEA (0.1 mL, 0.6 The above amine hydrochloride salt in DCM/DMF (7:3, 10.0 mL) was added. After 3 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness.

Step 3

The unpurified product was then dissolved in anhydrous dichloromethane (8.0 mL) and EtOAc (127 mg, 0.3 m. The reaction mixture was then stirred at room temperature for 2 hours, and 0.26 mole Na ₂ S was cooled saturated NaHCO _{3 2} O ₃ and extracted with ethyl acetate (3x). And washed with saturated NaHCO ₃ (2x) and brine (1x) washing the ethyl acetate layer was combined. Production level was purified by HPLC to obtain a HPLC purity of> 95% of 1- [2 S - (3- tert-butyl ureido) -3,3-dimethyl-butyl acyl] -4 R - (6- methoxy isoquinolin-l-yloxy) pyrrolidine -2 S - carboxylic acid (2-cyclopropyl-aminocarbonyl -1 S - methyl -2-oxoethyl cyclopropylmethyl) Amides (23). MS m / z 679 (M ⁺ +H), 701 (M ⁺ +Na), 677 (M ⁺ -H)

Example 11

Synthesis of 1-[2 S -(3-tert-butylureido)-3,3-dimethylbutanyl]-4 R -(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-2 S -formic acid (2-cyclopropylaminocarbonyl-1 S -cyclopropylmethyl- 2S -sideoxyethyl)decylamine (26)

step 1

Ethyl chloroformate (4.3 ml, 44.5 mmol) was added dropwise to 3-ethoxycinnamic acid (5.71 g, 29.7 mmol) and triethylamine (8.3 ml) in acetone (35 mL) at 0 °C. , 59.4 millimoles) solution. After 1 hour at 0 ° C, aqueous sodium azide (3.1 g, 47.5 mmol, 16 mL water) was added dropwise and then the mixture was stirred at 23 ° C for 16 hours. Water (50 mL) was added to the mixture and the volatiles were removed in vacuo. The organic layer with toluene (3x25 mL) and then dried to produce the sludge (MgSO ₄₎ binding. The dried solution was filtered and then added dropwise to a solution of diphenylmethane (25 mL) and tributylamine (14.2 mL, 59.4 mmol) at 190 °C. The added toluene was distilled off. After all the additions were completed, the reaction temperature was raised to 210 ° C for 2 hours. After cooling, the precipitated product was collected by filtration and washed with hexanes and dried under vacuo to yield 6-ethoxy-2H-isoquinolin-1-one (1.92 g, 10.2 mmol, 34% yield). MS m / z 190 (M ⁺ +H)

Step 2

A suspension of 6-ethoxy-2H-isoquinolin-1-one (896 ml, 4.74 mmol) in POCl ₃ (4 mL) was heated to 110 ° C for 3 hours (a transparent solution was produced upon heating) ). After 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was poured into ice water (10 mL), and then adjusting the pH to 10 followed by NaOH and extracted with CHCl ₃ (3x25 mL) to 3 equivalents. In conjunction brine CHCl ₃ layer was dried (MgSO _4). The organic layer was then filtered and concentrated to give 1-chloro-6-ethoxyisoquinoline as a tan solid ( </ RTI></RTI></RTI></RTI></RTI><RTIgt; MS m / z 208 (M ⁺ +H)

Step 3

At 23 ℃ within 15 minutes to potassium t-butoxide (774 mg, 6.9 mmol) was added in small portions DMSO commercially available N (20 mL) - the third -Boc- (2 S, 4 R) - Hydroxyproline (531 mg, 2.30 mmol). The mixture was stirred at 23 ° C for 30 minutes and then cooled to 0 ° C. 1-Chloro-6-ethoxyisoquinoline (500 mg, 2.41 mmol) was added in small portions over 10 minutes at 0 °C. The reaction mixture was stirred at 23 ° C for 16 hours. The obtained suspension was poured into water, and then the mixture was washed with ether (2x) and ethyl acetate (2x). The aqueous layer was acidified to pH~4 with aq. 1 EtOAc then extracted with DCM (3x). In conjunction brine DCM layer was then dried (MgSO _4). The organic layer was filtered and concentrated to give ( 2S , 4R )-(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-1,2-dicarboxylic acid-1-tributyl ester (24) ) (coarse weight = 1.18 g, >90% purity). MS m / z 403 (M ⁺ + H), 401 (M ⁺ -H), 303 (M ⁺ -Boc). It was used in the next step for the crude material which was not further purified.

Step 4

(2 S ,4 R )-(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester (114 mg, 0.28 mmol) , HATU (128 mg, 0.34 mmol) and DIPEA (0.15 mL, 0.84 mmol) were added to ( S )-3-amino-4, N -di in DCM/DMF (10:3, 13 mL) Cyclopropyl-2-hydroxybutyrate hydrochloride (66 mg, 0.28 mmol). After 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness to obtain 2 S - (2- cyclopropyl-aminocarbonyl -1 S - cyclopropylmethyl-2-hydroxyethyl amine-carbonyl) -4 R -(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (25).

Step 5

Will be two 4.0 equivalents of HCl in alkane (10 ml) was added to the above unpurified compound. After 1 hour, the reaction mixture was concentrated and dried to give the corresponding crude salt as a white solid. 2S-(3-tert-butylureido)-3,3-dimethylbutyric acid (64 mg, 0.28 mmol), HATU (128 mg, 0.34 mmol) and DIPEA (0.15 mL, 0.84 m) The above amine hydrochloride salt was added to DCM/DMF (10:3, 13 mL). After 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness.

Step 6

The unpurified product was then dissolved in anhydrous dichloromethane (10.0 mL) and EtOAc (EtOAc &lt;RTIgt; The reaction mixture was then stirred at rt for 1 h, saturated NaHCO 0.26 molar Na ₂ S ₂ O _{3 3} cooling and extracted with EtOAc (3x). And washed with saturated NaHCO ₃ (2x) and brine (1x) The combined EtOAc layer is washed, then dried (MgSO _4). Then by flash chromatography (65% ethyl acetate / hexanes) filtered, concentrated, and the organic layer was purified to obtain a white solid of 1- [2 S - (3- tert-butyl ureido) -3,3 Dimethyl decyl]-4 R -(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-2 S -carboxylic acid (2-cyclopropylaminocarbonyl-1 S -cyclopropylmethyl-2 S - Side oxyethyl) decylamine (26) (80.7 mg, 0.116 mmol, 42% yield). ¹ H NMR: (DMSO) 8.67 (d, 1H, J = 5.6 Hz); 8.26 (d, 1H, J = 6.8 Hz); 8.06 (d, 1H, J = 8.8 Hz); 7.89 (d, 1H, J) =5.6Hz); 7.24~7.22(m,1H); 7.01~6.98(dd,1H,J=2.4,8.8Hz); 5.90~5.85(m,2H);5.65~5.62(m,1H);5.06~ 5.01(m,1H); 4.53(t,1H,J=8.0Hz); 4.26~4.23(m,1H);4.16~4.08(m,3H);3.84~3.80(m,1H);2.69~2.65( m,1H);2.11~2.04(m,1H);1.64~1.57(m,1H);1.35~1.29(m,3H);1.15(m,9H);0.91(m,9H);0.89~0.81( m, 3H); 0.61 to 0.48 (m, 4H); 0.36 to 0.27 (m, 2H). MS m / z 693 (M ⁺ +H), 715 (M ⁺ +Na), 691 (M ⁺ -H)

Example 12

Synthesis of 1-[2 S -(3-tert-butylureido)-3,3-dimethylbutanyl]-4 R -(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-2 S -formic acid (1 S -cyclopropylamine oxalylbutyl) decylamine (28)

step 1

Will be two 4.0 equivalents of HCl in alkane (6.0 mL) was added to [ 1S- (cyclopropylaminecarbonylhydroxymethyl)butyl]carbamic acid tert-butyl ester 75 mg, 0.26 mmol. After 1 hour, the reaction mixture was concentrated and dried to give the corresponding crude salt as a white solid. (2 S ,4 R )-(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester (106 mg, 0.26 mmol) HATU (119 mg, 0.31 mmol) and DIPEA (0.15 mL, 0.78 mmol) were added to the above amine hydrochloride salt in DCM/DMF (10:3, 13 mL). After 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness to obtain 2 S - [1 S - (carbonyl cyclopropylamine hydroxymethyl) butylamine carbonyl] -4 R - (6- ethoxy Isoquinolin-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (27).

Step 2

Will be two 4.0 equivalents of HCl in alkane (10 ml) was added to the above unpurified compound. After 1 hour, the reaction mixture was concentrated and dried to give the corresponding crude salt as a white solid. 2 S -(3-tert-butylureido)-3,3-dimethylbutyric acid (60 mg, 0.26 mmol), HATU (128 mg, 0.34 mmol) and DIPEA (0.15 mL, 0.84) The above amine hydrochloride salt in DCM/DMF (10:3, 13 mL) was added. After 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness.

Step 3

The unpurified product was then dissolved in anhydrous dichloromethane (10.0 mL) and EtOAc &lt;RTI ID=0.0&gt;&gt; After stirring at room temperature for 1 hour, it was cooled in 0.26 mol of Na ₂ S ₂ O ₃ in saturated NaHCO ₃ and the mixture was extracted with ethyl acetate (3×). And washed with saturated NaHCO ₃ (2x) and brine (1x) washing the combined ethyl acetate layer was then dried (MgSO _4). Then by flash chromatography (65% ethyl acetate / hexanes) filtered, concentrated, and the organic layer was purified to obtain a white solid of 1- [2 S - (3- tert-butyl ureido) -3,3 Dimethyl decyl]-4 R -(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-2 S -carboxylic acid (1 S -cyclopropylamine oxalylbutyl) decylamine (28) (75.7 mg, 0.11 mmol, 43% yield). ¹ H NMR: (DMSO-d ₆ ) 8.75 (d, 1H, J = 4.8 Hz); 8.28 (d, 1H, J = 7.2 Hz); 8.13 (d, 1H, J = 8.8 Hz); 7.96 (d, 1H, J=6.0Hz); 7.31~7.29(m,2H); 7.10~7.06(dd,1H,J=2.4,9.2Hz); 5.94~5.92(m,2H); 5.72~5.70(m,1H) ;5.04~5.00(m,1H);4.58(t,1H,J=7.6Hz);4.34~4.30(m,1H);4.23~4.17(m,3H);3.90~3.86(m,1H);2.79 ~2.74(m,1H);2.54~2.51(m,1H);2.18~2.11(m,1H);1.77~1.70(m,1H);1.48~1.38(m,3H);1.15(m,9H) ; 0.91 (m, 9H); 0.89 to 0.86 (m, 3H); 0.69 to 0.59 (m, 4H). MS m/z 681 (M ⁺ +H), 703 (M ⁺ +Na), 679 (M ⁺ -H)

Example 13

Synthesis of 1-[ 2S- (3-tert-butylureido)-3,3-dimethylbutylidene]-4 R- (6-methoxyisoquinolin-1-yloxy)pyrrolidine-2 S -formic acid (1 S -cyclopropylamine oxalylyl) decylamine (30)

step 1

(2 S ,4 R )-(6-Methoxyisoquinolin-1-yloxy)pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester (157 mg, 0.40 mmol) (S)-3-Amino-2-hydroxyheptanoic acid in DCM/DMF (10:3, 13 mL), HATU (200 mg, 0.53 mmol) and DIPEA (0.35 mL, 2.0 mmol) Cyclopropylamine hydrochloride (96 mg, 0.40 mmol). After 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness to obtain 2 S - [1 S - (carbonyl-cyclopropylamine - (±) - hydroxymethyl) pentyl amine carbonyl] -4 R - ( 6-Methoxyisoquinolin-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (29). MS m / z 571 (M ⁺ +H), 593 (M ⁺ +Na), 569 (M ⁺ -H), 471 (M ⁺ -Boc)

Step 2

Will be two 4.0 equivalents of HCl in alkane (10 ml) was added to the above unpurified compound. After 1 hour at room temperature, the reaction mixture was concentrated and dried to give the corresponding white salt. 2 S -(3-tert-butylureido)-3,3-dimethylbutyric acid (93 mg, 0.40 mmol), HATU (200 mg, 0.53 mmol) and DIPEA (0.35 mL, 2.0 The above amine hydrochloride salt in DCM/DMF (10:3, 13 mL) was added. After 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl (2×), NaHCO ₃ (1×) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness. MS m / z 683 (M ⁺ +H), 705 (M ⁺ +Na), 681 (M ⁺ -H)

Step 3

The unpurified product was then dissolved in anhydrous dichloromethane (10.0 mL) and EtOAc (br. The reaction mixture was then stirred at room temperature for 2 hours, and 0.26 mole Na ₂ S was cooled saturated NaHCO _{3 2} O ₃ and extracted with ethyl acetate (3x). And washed with saturated NaHCO ₃ (2x) and brine (1x) washing the combined ethyl acetate layer was then dried (MgSO _4). The organic layer was then filtered, concentrated and purified by flash chromatography (45% ethyl acetate /hexane) to afford 1-[ 2S- (3-t-butylureido)-3,3- Dimethyl decyl]-4 R -(6-methoxyisoquinolin-1-yloxy)pyrrolidine-2 S -carboxylic acid (1 S -cyclopropylamine oxalylyl) decylamine (30) (83.5 mg, 0.12 mmol, 31% yield). ¹ H NMR: (DMSO) 8.74 (d, 1H, J = 4.8 Hz); 8.27 (d, 1H, J = 7.2 Hz); 8.15 (d, 1H, J = 9.2 Hz); 7.97 (d, 1H, J) =6.0Hz);7.33~7.31(m,2H);7.10~7.08(dd,1H,J=2,8.8Hz);5.96(s,1H);5.94(d,1H,J=9.6Hz);5.71 ~5.69(m,1H); 5.02~4.98(m,1H); 4.60(t,1H,J=8.4Hz); 4.34~4.22(m,1H); 4.23(d,1H,J=9.2Hz); 3.91(s,3H);3.90~3.87(m,1H);2.78~2.73(m,1H);2.54~2.51(m,1H);2.17~2.11(m,1H);1.77~1.72(m,1H) ); 1.43~1.33 (m, 5H); 1.20 (m, 9H); 0.95 (m, 9H); 0.88 to 0.85 (m, 5H); 0.69 to 0.58 (m, 4H). MS m / z 681 (M ⁺ +H), 703 (M ⁺ +Na), 680 (M ⁺ -H)

Example 14

step 1

3-cyclopropyl-6-methoxyisoquinoline (32). Treatment of 2,2,6,6-tetramethylhexahydropyridine (1.0 g, THF (17 ml) by dropwise addition of n-butyllithium (1.6 g in hexane; 8.0 mmol) at -15 °C. The method of 7.0 millimoles) produces tetramethylpiperidide. After 15 minutes at -15 ° C, a solution of cyclohexyl (4-methoxy-2-methylbenzylidene)amine (660 mg, 2.86 mmol) in THF (3 mL) was added dropwise. A purple solution. The reaction mixture was warmed to 0 ° C over 20 min then a portion of THF (2 mL) of N -methyl- N -methoxycyclopropanecarbamide (630 mg, 4.4 mmol) was added at 0 °C. ).

Step 2

1-Chloro-3-cyclopropyl-6-methoxyisoquinoline (34). 3-Cyclopropyl-6-methoxyisoquinoline (32) was dissolved in dichloromethane (8 mL) then cooled to 0. This solution was treated with a solution of m-chloroperbenzoic acid (mCPBA; 412 mg, 2.4 mmol) in dichloromethane (8 ml), and then the mixture was stirred at room temperature for 2 hr. The reaction mixture was cooled with dimethyl sulfite (100 μL) and then stirred for additional 15 min. The mixture was treated with saturated aqueous sodium bicarbonate (20 mL) and then evaporated. Aqueous phase was extracted with dichloromethane, and then in vacuo Chromatography (SiO _2; 10% MeOH in CH ₂ Cl ₂₎ and dried, to obtain 405 mg (94%) of 3-cyclic organic phases were combined and concentrated by N -oxide (33) of propyl-6-methoxyisoquinoline.

The N - oxide was dissolved in dichloromethane (5 ml), followed by addition of 1 ml POCl _3. The mixture was heated under reflux for 2 hours, cooled and poured onto ice. The pH of the mixture was adjusted to 8 with NH ₄ OH, and then the obtained solution was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried and concentrated in vacuo. By chromatography (SiO _2; hexanes / EtOAc, 4: 1) purification of the crude product was obtained 310 mg (66% total) of the title compound.

Step 3

1- N- Boc-4-3-cyclopropyl-6-methoxyisoquinolin-1-yloxy)pyrrolidine-2-carboxylic acid (37). N- Boc-4-hydroxy-L-proline (A; 192 mg, 830 micromolar) was dissolved in DMSO (5 mL) at room temperature, followed by the addition of potassium tert-butoxide (270 mg, 2.4). Millions of ears). The obtained solution was stirred at room temperature for 1.5 hours, then 1-chloro-3-cyclopropyl-6-methoxyisoquinoline (4; 192 mg, 820 micromoles) was added. The obtained solution was stirred overnight, diluted with 15 ml of 5% aqueous citric acid and then extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried and concentrated in vacuo to afford 375 g of N- Boc-4-hydroxy-L-proline acid (35).

The unpurified aryl ether was dissolved in DMF (2 mL) and then (O-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate was added. Ester (HATU; 380 mg, 830 micromolar) followed by 3-( S )-amino-2-( RS )-hydroxycaproic acid- N -cyclopropylcarbamamine hydrochloride (36; 190 mg) , 830 micromolar) and N,N -diisopropylethylamine (DIPEA; 800 microliters). The resulting mixture was stirred overnight and then diluted with water. The obtained precipitate was filtered, washed with water and dried to give 460 mg (yel.

Step 4

1-[2 S -(3-tert-butylureido)-3,3-dimethylbutylidene]-4- R -(2-cyclopropyl-7-methoxyquinolin-4-yloxy Pyrrolidine-2( S) -formic acid (1-cyclopropylamine oxalylbutyl) decylamine hydrochloride (40). Dissolve the compound in 1,4-two 4.0 equivalents of HCl in alkane (2 mL) was then stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo then EtOAcqqqqqqq ( S )-2-(3-tert-butylureido)-3,3-dimethylbutyric acid (C; 100 mg, 440 micromoles), HATU (200 mg, 520 micromoles) and DIPEA This solution was treated (800 ml). The reaction mixture was diluted with water and then the obtained precipitate was filtered, washed with water and dried to give 250 mg (80%) of corresponding 2-hydroxycarbamide 39. The solid was dissolved in dichloromethane (20 mL) and then 1,1,1-tris(ethyloxy)-1,1-dihydro-1,2-benzidion Treatment with leuco-3-(1H)-one (D; 220 mg, 660 micromolar). The reaction mixture was stirred at room temperature for 2 hours. The solution was diluted with diethyl ether (40 mL) was added followed by saturated Na ₂ S ₂ O ₃ solution (10 ml) and 10 ml aqueous NaHCO ₃ (10 mL). The biphasic mixture was stirred for 10 minutes and then the layers were separated. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried and concentrated in vacuo. The residue was purified by chromatography (SiO ₂ hexane / EtOAc, 1:1), then EtOAc EtOAc EtOAc EtOAc Hydrochloride. Mass spectrometry (M+Na) 705

Example 15

step 1

4-Ethyl-6-methoxyisochroman-1,3-dione (42). 2-Carboxymethyl-4-methoxybenzoic acid (41; 1.0 g, 4.8 mmol) was dissolved according to the procedure described in the literature ( Ind. J. Chem. B. 1986, 25B, 640-643 ) A mixture of pyridine (1.4 ml) and acetic anhydride (8.6 ml, 9.3 g, 91 mmol) was then stirred for 3 hours during solid formation. The suspension was diluted with diethyl ether, filtered and the cake was washed with diethyl ether. Yield: 905 mg (81%) of the title compound.

Step 2

6-Methoxy-3-methyl-2 H -quinolin-1-one (43). The cyclic anhydride 42 (405 mg, 1.73 mole) was dissolved in the aqueous NH ₄ OH, then heated at reflux for 1.5 hours. After the mixture was cooled to room temperature, the solid was filtered and dried overnight to afford 270 mg (yield:

Step 3

1-Chloro-6-methoxy-3-methylisoquinoline (44). Isoquinolin-1-one 43 was dissolved in POCl ₃ (2.5 ml), and then heated under reflux for 1 hour. Excess POCl ₃ was removed in vacuo and the residue was dissolved in CHCl ₃ . The obtained solution was washed with 1 equivalent of an aqueous NaOH solution, water and a saturated aqueous solution of sodium chloride. The solvent was evaporated to give the crude product 44 used directly in the next step.

Step 4

1- N- Boc-4-(6-methoxy-3-methylisoquinolin-1-yloxy)pyrrolidine-2-carboxylic acid (45). 1-N-Boc-4-hydroxy-L-proline (A; 281 mg, 1.21 mmol) was dissolved in DMSO (3 mL) at room temperature followed by the addition of potassium tributoxide (270 mg) , 2.4 millimoles). The obtained solution was stirred at room temperature for 2 hours and then cooled to 0 °C. The isoquinoline solution 14 in DMSO (3 ml) was then added dropwise to a cold solution of A and potassium tert-butoxide (t-BuOK), and then the mixture was allowed to warm to room temperature. The solution was stirred for 16 hours, then an additional 0.2 equivalent of A was added and the mixture was stirred for an additional 1.5 hours. The reaction mixture was acidified to pH = 4 with 5% aqueous EtOAc. The solution was extracted with ethyl acetate, and then the organic phase was washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase was concentrated in vacuo to give the title compound.

Step 5

1- N- Boc-2-[1-(cyclopropylaminecarbonylhydroxymethyl)butylaminecarbonyl]-4-(6-methoxy-3-methyl-isoquinolin-1-yloxy Pyrrolidine (47). Compound 45 (196 mg, 487 micromoles) was converted to the title compound in the same procedure as described for compound 5. Pyrrolidine 47 (210 mg, 77% yield) was used in the next step without further purification.

Step 6

1-[2 S -(3-tert-butylureido)-3,3-dimethylbutylidene]-4 R -(7-methoxy-2-methylquinolin-4-yloxy)pyrrole Pyridine-2-carboxylic acid (1-cyclopropylamine oxalylbutyl) decylamine (50). Compound 47 (210 mg, 368 micromoles) was converted to the corresponding hydrochloride salt as described for compound 48. Hydrochloride 48 was converted to the tripeptide 49 using intermediate C and HATU using the same conditions as compound 39. Finally, 49 was converted to the title compound α-ketoguanamine 50 using D in dichloromethane in the same manner as described above for the conversion of 39 to 40. By chromatography (SiO _2; 45% ethyl acetate in hexanes) to produce 85 mg of crude product 50 (34% from 17). Mass Spectrum (M+) 680.

Example 16

Synthesis of 1-[2 S -(3-tert-butylureido)-3,3-dimethylbutylidene]-4 R -(7-methoxy-2-pyrazole-1-ylquinoline-4- Alkoxypyrrolidine-2 S -formic acid (1 S -cyclopropylamine oxalylbutyl) decylamine (7): an alternative route for compound 7

step 1

4-Hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline in POCl ₃ (5.0 g, 26.17 mmol) (Faber K. et al., J. Heterocyclic. Chem. 1985 , 22, 1080) The suspension was heated to 115 ° C for 3 hours (a clear solution was produced upon heating). After 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was poured into ice water (40 mL), pH was adjusted to 10 with 3N NaOH and then extracted with CHCl ₃ (3×100 mL). In brine CHCl ₃ layer was combined, and then dried (MgSO _4). The organic layer was filtered and concentrated to give 2,4-dihydro-7-methoxyquinoline (4.9 g, 21.49 mmol, 82% yield). MS m / z 229 (M ⁺ +H)

Step 2

The solid pyrazole (3.2 g, 47.36 mmol, 3.0 equivalents) was heated and melted to 80 °C. A solid of 2,4-dihydro-7-methoxyquinoline (3.6 g, 15.78 mmol, 1.0 eq.) was added and the mixture was then warmed to &lt The mixture was cooled to room temperature and then purified by flash chromatography (20% ethyl acetate /hexane) to afford 4-chloro-7-methoxy-2-pyrazol-1-ylquinoline as a white solid. (2.3 g, 8.88 mmol, 56% yield). ¹ H NMR (CDCl ₃ ): 8.77 (d, 1H, J = 2.8 Hz); 8.18 (s, 1H); 8.10 (d, 1H, J = 9.2 Hz); 7.79 (s, 1H); 7.38 (d, 1H, J = 2.8 Hz); 7.23 (dd, 1H, J = 2.0, 8.8 Hz); 6.53 to 6.52 (m, 1H); 3.98 (s, 3H). MS m / z 260 (M ⁺ +H)

Step 3

At 23 ℃ within 15 minutes to potassium t-butoxide (1.9 g, 16.6 mmol) in small portions was added the commercially available N in DMSO (20 ml) - a third -Boc- (2 S, 4 R) - Hydroxyproline (1.53 g, 6.64 mmol). The mixture was stirred at 23 ° C for 1.5 hours, then 4-chloro-7-methoxy-2-pyrazol-1-ylquinoline (1.9 g, 7.30 mmol) was added in small portions over 15 min. The reaction mixture was stirred at 23 ° C for 16 hours. The obtained suspension was poured into water (150 ml), and the mixture was washed with ethyl acetate (2×100 ml). 1 equivalent of aqueous HCl and the aqueous layer was acidified to pH ~ 4, and extracted with CHCl ₃ (3x100 mL). In brine CHCl ₃ layer was combined, and then dried (MgSO _4). And filtered to obtain (2 S, 4 R) organic layer was concentrated - (7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy) pyrrolidine-1,2-dicarboxylic acid -1 - Tert-butyl ester (2.7 g, 5.95 mmol, 90% yield). MS m / z 455 (M ⁺ + H), 453 (M ⁺ -H), 355 (M ⁺ -Boc). This material was used for the crude material which was not further purified in the next step.

Step 4

Will be two 4.0 equivalents of HCl in alkane (13 ml) was added to [ 1S- (cyclopropylaminecarbonylhydroxymethyl)butyl]carbamic acid tert-butyl ester (1.05 g, 3.67 mmol). After 1 hour, the reaction mixture was concentrated and dried to give the corresponding crude salt as a white solid. (2 S ,4 R )-(7-Methoxy-2-pyrazol-1-ylquinolin-4-yloxy)pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester ( 1.66 g, 3.67 mmol, HATU (1.67 g, 4.40 mmol) and DIPEA (2.6 mL, 14.08 mmol) were added to the above amine hydrochloride salt in DCM/DMF (3:1, 60 mL). After 1 hour at room temperature, it was diluted with ethyl acetate (100 mL) and washed with 1N EtOAc (2×50 mL), NaHCO ₃ (1×100 mL) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness to obtain 2 S - [1 S - (carbonyl cyclopropylamine hydroxymethyl) butylamine carbonyl] -4 R - (7- methoxy Non-imagewise isomeric mixtures of tert-butyl 2-pyrazol-1-ylquinolin-4-yloxy)pyrrolidine-1-carboxylate. This material was used for the crude material which was not further purified in the next step.

Step 5

Will be two 4.0 equivalents of HCl in alkane (15 ml) was added to the above compound. After 1 hour, the reaction mixture was concentrated and dried to give the corresponding crude salt as a white solid. 2 S -(3-tert-butylureido)-3,3-dimethylbutyric acid (848 mg, 3.67 mmol), HATU (1.67 g, 4.40 mmol) and DIPEA (2.6 mL, 14.08) The above amine hydrochloride salt in DCM/DMF (3:1, 60 mL) was added. After 1 hour at room temperature, it was diluted with ethyl acetate (100 mL) and washed with 1N EtOAc (2×50 mL), NaHCO ₃ (1×100 mL) and brine (1×). Dried (MgSO _4), filtered, and the ethyl acetate layer was evaporated to dryness. This material was used for the crude material which was not further purified in the next step.

Step 6

The crude product was then dissolved in dry dichloromethane (25 mL) and EtOAc (EtOAc, &lt After stirring at room temperature for 1 hour, it was cooled in 0.26 mol of Na ₂ S ₂ O ₃ in saturated NaHCO ₃ and the mixture was extracted with dichloromethane (3×). And washed with saturated NaHCO ₃ (2x) and brine (1x) washing the combined dichloromethane layer was then dried (MgSO _4). Filtration, concentration and purification of the organic layer by flash chromatography (60% ethyl acetate /hexane) afforded 1-[ 2S- (3-t-butylureido)-3,3- Butyl sulfhydryl]-4 R -(7-methoxy-2-pyrazol-1-ylquinolin-4-yloxy)pyrrolidin-2 S -carboxylic acid (1 S -cyclopropylamine oxazinidine Base amide (7) (1.6 g, 2.18 mmol, 60% yield). ¹ H NMR: (DMSO-d ₆ ) 8.76~8.70 (m, 2H); 8.22 (d, J = 6.8 Hz, 1H); 8.11 (d, J = 9.6 Hz, 1H); 7.87 (d, J = 1.2) Hz, 1H); 7.45 (s, 1H); 7.27 (d, J = 2.4 Hz, 1H); 7.00 to 6.97 (dd, J = 2.8 and 9.6 Hz, 1H); 6.64~6.62 (m, 1H); 5.92 (brs, 1H); 5.49 (brs, 1H); 5.00 to 4.96 (m, 1H); 4.55 to 4.49 (m, 2H); 4.18 (d, J = 5.6 Hz, 1H); 3.90 (s, 3H); 3.91~3.82(m,1H);3.54(brs,1H);2.75~2.72(m,1H);2.54~2.51(m,1H);2.17~2.14(m,1H);1.69~1.66(m,1H) ); 1.40~1.34 (m, 3H); 1.13 (m, 9H); 0.93 (m, 9H); 0.90 to 0.82 (m, 3H); 0.65 to 0.53 (m, 4H). MS m / z 733 (M ⁺ +H), 755 (M ⁺ +Na), 731 (M ⁺ -H)

Biological example Example 1 Replicon detection of HCV

The HCV replicon assay is a cell culture system that mimics the replication of HCV in vivo and provides a system for studying HCV replication in vitro. It is used to transfer infection-derived viral RNA derived from a consensus HCV genomic sequence into human Huh7 hepatoma cells that have been allowed to replicate in semi-transmissible RNA viruses (Lohmann V., Korner F., Koch J.-O., Herian U., Theilmann). L. and Bartenschlager R. (1999). Replication of subgenomic C-type RNA hepatitis virus in liver cancer cell lines, Science 285, 110-113 and Blight KJ, Kolykhalov AA and Rice CM (2000), initiation of HCV RNA replication in cell culture Efficiency, Science 290, 972~1974). These metastatic infected cell lines contain a subgenome of the HCV RNA genome comprising (1) HCV 5'NTR fused to 12 amino acids in the capsid coding region; (2) a neomycin phosphotransferase gene as a selectable marker (Neo); (3) an internal saccharide insertion site (IRES) from the encephalomyocarditis virus (EMCV) that directly translates HCV non-structural proteins (various NS2 or NS3 to NS5B); and (4) 3'NTR. HCV RNA containing auto- and sustained replication of replicon-containing cells can be quantitatively detected by real-time qPCR. Thus, the replication system can quantitatively detect antiviral activity by monitoring changes in HCV RNA replication in cell assays.

Replicon-containing HCV cells (Huh7/A selection strain) were routinely maintained in the growth medium of A selection strain (DMEM medium [Invitrogen], adding 10% fetal bovine serum, 1% non-essential amino acid and 1 g/L G418). Test compounds were dissolved in dimethyl hydrazine (DMSO) prior to treatment to make a 200X stock solution as a full dose.

In the detection of HCV replicon, Huh7/A strain cells from culture flasks were digested with trypsin, and ⁴ ×10 ⁴ cells of G418-free A-selective growth culture solution were injected into each well in a 24-well culture dish. It was then incubated overnight in a humidified incubator at 37 °C. After overnight incubation, a solution of the same volume (5 microliters of 200x compound stock solution per well) was added to the wells to obtain a final concentration of 0.5% DMSO. Three of the wells were spiked with 5 microliters of DMSO as an untreated control. ₅₀ measurement IC, starting from a stock solution to three of the seven repeated sequences of diluted test compound. The plates were incubated at 37 ° C for 48 hours. After the cultivation, the collected cells were transferred to a 96-well culture plate, and total RNA was extracted using an RNA isolation kit (Rneasy 96, Qiagen) according to the manufacturer's 96-well disk nucleic acid assay manual (Qiagen).

Total RNA washed in 130 μl of Rnase-free distilled water was quantified by the RiboGreen assay according to the method of the supplier (Molecular Probe). Briefly, an equal amount of 5 microliters of RNA repeats were placed into 96-well black microplates and 96-well TaqMan optical glass plates. Mix 95 μl of diluted RiboGreen reagent (diluted 1:250 in TE buffer) with the RNA sample in the black microplate, then use the fluorescent microdisk reader at the standard fluorescence wavelength (excitation ~480 nm, emission ~520 The fluorescence of the sample is measured under the nanometer). Ribosome RNA (Molecular Probe) was used as a control standard.

Raqa TaqMan quantitative PCR (instant qPCR) quantifies the amount of HCV replicon RNA within each sample. The RT-qPCR reaction was carried out at 25 μl on an ABI PRISM 7900 HT Sequence Detection System (Applied Biosystems). The reaction mixture contained 5 microliters of total RNA (10-100 Ng), 1xTaqMan Buffer A (Applied Biosystems), 5.5 mg of MgCl ₂ , 1.2 mg of molecular dNTP mixture, and 0.625 units of AmpliTaq Gold (Applied Biosystems). 5 units of MMLV reverse transcript (Promega), 5 units of rRNasin (Promega), 300 ng of each of these forward and reverse primers, and 100 ng of TaqMan MGB probe. The primer and probe were designed to hybridize to a portion of the neomycin resistance gene (Neo) in the replicon and its sequence is as follows: forward primer 5'-GGCTACCTGCCCATTCGA-3'; reverse primer 5'-CCGGCTTCCATCCGAGTAC-3 ';MGB probe 5'CCACCAAGCGAAACA-3'. An immediate step was carried out at 48 ° C for 30 minutes followed by 10 minutes at 95 ° C. The thermal cycling procedure consisted of 40 cycles of 15 seconds at 95 °C and 1 minute at 60 °C. TaqMan raw data (Ct values) were analyzed using Sequence Detection System (SDS) software to mathematically convert to the number of HCV RNA genomes and the total RNA normalized to each sample. The concentration of HCV replicon RNA in the sample without compound treatment as a control group and untreated cells was defined as 100%. The inhibitory activity of the compound was determined by treating the ratio of the amount of normalized HCV RNA in the sample to the untreated control. The IC _{5 0 of the} compound was calculated using a standard 4-parameter curve adaptation mode.

Compounds of the invention measured by the above-described assay and observed for inhibition of HCV replication to IC _{5 0} <100 micromolar. 3, 6 and 7, compound on HCV replication inhibition is IC _{5 0} <50 micromolar; 1,2,5,8 ~ 13 while inhibitory effects of compounds on HCV replication and 15 to IC _{5 0} <10 Micro Mo Ear concentration.

Example 1

Representative pharmaceutical formulations containing a compound of formula (I): Oral formulation Compounds of formula (I) 10 to 100 mg of citric acid monohydrate 105 mg of sodium hydroxide 18 mg of flavoring water sufficient to 100 ml

Intravenous formulation of compound of formula (I) 0.1~10 mg of glucose monohydrate sufficient amount of isotonic citric acid monohydrate 1.05 mg of sodium hydroxide 0.18 mg of water for injection sufficient amount to 1.0 ml

Tablet Formulation Compound of Formula (I) 1% Microcrystalline Cellulose 73% Stearic Acid 25% Silicone 1%

The invention is described by way of a more detailed description and embodiments for the purpose of clarity. It will be apparent to those skilled in the art that various changes and modifications can be applied within the scope of the appended claims. Therefore, the above description should be understood as illustrative only and not limiting. Accordingly, the scope of the invention is not intended to

Claims (20)

A compound of formula (I): Wherein: E is -COCONHR ⁶ , wherein R ⁶ is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, C _6-18 aralkyl or C _6-18 heteroarylalkyl, wherein The aromatic group is optionally substituted by 1 or 2 halogens, wherein the halogen is selected from fluorine, chlorine, bromine or iodine; R ¹ is C _1-8 alkyl, halogen C _1-8 alkyl, C _{2 - 6} alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl C _1-8 alkyl, C _6-10 aryl, C _6-18 aralkyl, C _6-10 heteroaryl, C _{6 a -18} heteroaralkyl group, a C _3-8 heterocyclic group or a C _3-8 heterocyclic C _1-8 alkyl group, wherein the aliphatic, alicyclic and aromatic groups in R ¹ are optionally 1 or 2 independently selected from hydroxy, C _1-8 alkoxy, C _6-18 aryloxy, C _6-18 heteroaryloxy, C _1-8 alkylthio, C _6-10 arylthio, C _{6 -10} heteroarylthio, amine, monosubstituted amine, disubstituted amine, C _1-8 alkylsulfonyl, C _6-10 arylsulfonyl, C ₁ carboxyl, C _1-8 alkoxy R ^b substitution of a carbonyl group, a C _1-8 guanylamino group, an amine carbonyl group, a halogen or a cyano group, and further wherein the aromatic or aliphatic ring system in R ^b is optionally 1, 2 or 3 independently selected from C _1-8 alkyl, C _1-8 alkoxy, halogen, halogen C _1-8 alkyl, halogen C _1-8 alkoxy, C ₁ carboxyl or C ₁ carboxyl C _{1- 8} alkyl substituents; wherein C _6-10 heteroaryl, C _6-18 heteroaralkyl, C _6-18 heteroaryloxy, C _6-10 heteroaryl group, C _3-8 heterocyclyl Or a C _3-8 heterocyclic C _1-8 alkyl group containing an alicyclic or aromatic ring wherein 1, 2 or 3 ring atoms are selected from N, O or S, and the remaining ring atomic carbon X is -O-; R ³ is C _1-8 alkyl, halo C _1-8 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _{3- 8} -cycloalkyl C _1-8 alkyl, C _6-10 aryl, C _6-18 aralkyl, C _6-10 heteroaryl, C _6-18 heteroarylalkyl, C _3-8 heterocyclic Or a C _3-8 heterocyclic C _1-8 alkyl group, wherein the aliphatic, alicyclic and aromatic groups in R ³ are optionally 1 or 2 independently selected from hydroxy, C _1-8 alkoxy Halogen C _1-8 alkoxy, C _6-18 aryloxy, C _6-18 heteroaryloxy, C _1-8 alkylthio, C _6-10 arylthio, C _6-10 heteroaromatic sulfur Base, amine group, monosubstituted amine group, disubstituted amine group, C _1-8 alkylsulfonyl group, C _6-10 arylsulfonyl group, carboxyl group, C _1-8 alkoxycarbonyl group, decylamino group, amine R ^c substitution of a carbonyl, halogen or cyano group, and further wherein the aromatic or aliphatic ring system within R ^c is optionally 1, 2 or 3 independently selected from C _1-8 alkyl, Substituted with a substituent of a C _1-8 alkoxy group, a halogen, a halogen C _1-8 alkyl group, a C ₁ carboxyl group or a C ₁ carboxy C _1-8 alkyl group; Y is -NH-C(O)NH-; R ² For the base of formula (a): Wherein: R ^d1 is hydrogen, hydroxy, C _1-8 alkoxy, amine, C _1-8 alkylamino or C _1-8 dialkylamino; R ^d and R ^{d2 are} independently hydrogen, C _{1- An} alkyl group, a halogen, a C _1-8 alkoxy group, a C _1-8 alkylthio group or a C _1-8 alkylsulfonyl group; and R ^d3 is a group of the formula: Optionally substituted with a halogen: C _1-8 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-8 alkyl, C _1-8 alkoxy, C _{3 -8} cycloalkoxy, nitro, C _1-8 alkylcarbonylamino, C _3-8 cycloalkylcarbonylamino, C _3-8 cycloalkyl C _1-8 alkylcarbonylamino, C _{1 -8} alkoxycarbonylamino group, amine group, C _1-8 alkylamino group, C _1-8 dialkylamino group or C _3-8 cycloalkylamino group, C _3-8 cycloalkylalkylamino group, - NHCONRR', wherein R is hydrogen or alkyl and R' is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl or C _3-8 cycloalkyl C _1-8 alkyl, wherein C _3-8 a cycloalkyl group and a C _3-8 cycloalkyl C _1-8 alkyl group are optionally substituted by 1, 2 or 3 C _1-8 alkyl groups; and R ⁴ is a C _1-8 alkyl group; or a pharmaceutical thereof Acceptable salts. A compound according to claim 1, wherein R ^{d3 is} optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, Tributyl, 2,2,-dimethylpropyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, ring Hexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl substituted. A compound according to claim 1, wherein R ^{d3 is} optionally substituted by an amine group, a methylamino group, an ethylamino group, an propylamino group, a 1-methylethylamino group or a 1,1-dimethylethylamine. Base, 2-methylpropylamino, 1-methylpropylamino, 2,2-dimethylpropylamino, 1,2-dimethylpropylamino, 1,1-dimethyl Alkylamino group, methylcarbonylamino group, ethylcarbonylamino group, propylcarbonylamino group, 1-methylethylamino group, 1,1-dimethylethylamino group, 2-methylcarbonylamino group, 1 -Methylpropylaminocarbyl, 2,2-dimethylaminocarbonyl, 1,2-dimethylpropylamino, 1,1-dimethylpropylamino, cyclopropylcarbonylamino, cyclobutyl Carbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, cyclopropylaminocarbonyl, cyclobutylmethylamino, cyclopentylcarbonylamino, cyclohexylmethylamino, methoxycarbonylamino , ethoxycarbonylamino, propoxycarbonylamino, 1-methylethoxycarbonylamino, 1,1-dimethyl-ethoxycarbonylamino, 2-methylpropoxycarbonyl, 1-methylpropoxycarbonyl Amine, 2,2-dimethylpropoxycarbonylamino, 1,2-dimethylpropoxycarbonylamino or 1,1-dimethylpropoxycarbonylamino. A compound according to claim 3, wherein R ^d1 is hydrogen, hydroxy, C _1-8 alkoxy, amine, C _1-8 alkylamino or C _1-8 dialkylamino; R ^d and R ^{D2 is} independently hydrogen, C _1-8 alkyl, halogen, C _1-8 alkoxy, C _1-8 alkylthio or C _1-8 alkylsulfonyl; and R ^d3 is hydrogen, C _{1- 8-} alkyl or C _3-8 cycloalkyl. A compound according to claim 3, wherein R ^d1 is hydrogen, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, n-propylamino, isopropylamine Base, dimethylamino, methylethylamino, methyl(n-propyl)amine or methyl(isopropyl)amine; R ^d and R ^{d2 are} independently hydrogen, fluorine, chlorine, methyl Ethyl, methoxy, ethoxy, methylthio or methylsulfonyl. A compound according to claim 3, wherein R ^d1 is hydrogen, hydroxy, methoxy or ethoxy; and R ^d and R ^{d2 are} independently hydrogen, fluoro, chloro or methyl. The compound of claim 1, wherein X is -O-; R ¹ is C _1-8 alkyl or C _3-8 cycloalkylalkyl; and R ³ is 1-methylethyl, 1- Methyl propyl, tert-butyl, cyclopropyl, phenyl or cyclohexyl. The compound of claim 1, wherein X is -O-; R ¹ is cyclobutylmethyl, ethyl or n-propyl; and R ³ is a third butyl or cyclohexyl group. A compound of claim 1, wherein E is -COCONHR ⁶ and R ⁶ is cyclopropyl. A compound having the following structure: Or a pharmaceutically acceptable salt thereof. A compound having the following structure: Or a pharmaceutically acceptable salt thereof. A non-image isomerized mixture of compounds represented by the following structures: Or a pharmaceutically acceptable salt thereof. A compound selected from the group consisting of 1-[2 S -(3-t-butylureido)-3,3-dimethylbutylidene]-4 R -(7-methoxy-2-pyridyl) Zin-1-yl-quinolin-4-yloxy)pyrrolidine-2 S -formic acid (1 S -cyclopropylamine oxalylbutyl) decylamine; 1-[2 S -(3-third Butylureido)-3,3-dimethylbutylidene]-4 R- (7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine-2 S -formic acid (1 S -cyclobutylmethyl-2-cyclopropylaminecarbonyl-2-oxoethyl) decylamine; {1 S -[2 S -(1 S -cyclopropylamine oxalylbutyl carbonyl) -4 R -(7-Methoxy-2-pyrazol-1-ylquinolin-4-yloxy)pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}aminocarboxylic acid Tributyl ester; {1 S -[2 S -(1 S -cyclopropylamine oxalylbutyl carbonyl)-4 R -(7-methoxy-2-phenylquinolin-4-yloxy) Tert-butyl pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}carbamic acid. A pharmaceutical composition comprising a compound as in claim 1 and one or more pharmaceutically acceptable excipients. A composition for treating hepatitis C infection comprising a compound as claimed in claim 1 and one or more pharmaceutically acceptable excipients. A compound according to claim 1 which is 1-[2 S -(3-t-butylureido)-3,3-dimethylbutylidene]-4 R- (7-methoxy-2- Pyrazol-1-yl-quinolin-4-yloxy)pyrrolidinium- 2S -formic acid (1 S -cyclopropylamine oxalylbutyl) decylamine and any non-image isomer thereof or its a mixture of mirror image isomers; or a pharmaceutically acceptable sulfuric acid or sulfonate thereof. A compound according to claim 1 which is 1-[2 S -(3-t-butylureido)-3,3-dimethylbutylidene]-4 R- (7-methoxy-2- Pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine- 2S -formic acid (1 R -cyclopropylamine oxalylbutyl) decylamine; or its sulfuric acid or methanesulfonate. A pharmaceutical composition for treating hepatitis C infection, comprising a compound as claimed in claim 9 and one or more pharmaceutically acceptable excipients. A pharmaceutical composition for treating hepatitis C infection comprising a compound as claimed in claim 10 and one or more pharmaceutically acceptable excipients. A compound selected from the group consisting of 1-[2 S -(3-t-butylureido)-3,3-dimethylbutylidene]-4- R- (2-cyclopropyl-7- Methoxyquinolin-4-yloxy)pyrrolidine-2( S) -formic acid (1-cyclopropylamine oxalylbutyl) decylamine hydrochloride; and 1-[2 S -(3- Ternyl butylurea)-3,3-dimethylbutylidene]-4 R- (7-methoxy-2-methylquinolin-4-yloxy)pyrrolidine-2( S )-carboxylic acid ( 1-cyclopropylammonium decyl butyl decylamine.